Dental Caries

Strep. Mutans
Fructans function as short term storage
reservoirs in the plaque and may also play a
role in bacterial adhesion to the tooth surface
Periodontal disease
Canker sores
 Canker Sores
Streptococci
Helicobacter pylori
Herpes Simplex
Varicella Zoster virus
Adenovirus
Cytomegalovirus
 Phagocytic and cytotoxic T cells probably aid in
destruction of oral epithelium that is directed and
sustained by local cytokine release.
Most recent research has centered on
dysfunction of the mucosal cytokine network.
Abnormal mucosal cytokine cascade in RAS
patients will lead to an exaggerated cell-mediated
immune response, resulting in localized
ulceration of the mucosa.
 During the initial period, a localised area of
erythema develops.
Within hours, a small white papule forms,
ulcerates, and gradually enlarges over the next
48 to 72 hours.
The individual lesions are round, symmetric,
and shallow, but no tissue tags are present
from ruptured vesicles.
Candidiasis
 It is caused by Candida Albicans.
Candida Albicans has special sets of glycosylphosphatidylinositol
(GPI)-linked cell surface glycoproteins that allow it to adhere to the
surfaces of microorganisms.
Candida with better adhesion potential are more pathogenic. The
yeasts penetration of the epithelial cells is facilitated by their
production of lipases, and for the yeasts to remain within the
epithelium, they must overcome constant desquamation of surface
epithelial cells.
Along with adhesion, Als3 proteins can function as invasins that
help with the invasion of C. albicans into host epithelial and
endothelial cells.
After the adherence of yeast cells to the surface, there is
development of hyphae cells in the upper part of the biofilm.
Eventually, this leads to a more resistant, mature biofilm and the
dispersion of yeast cells both contributing to the pathogens
virulence.
Oral Herpes
 Causes:
Herpes simplex 1 & 2
Varicella zoster virus
Esptein-Barr virus
Cytomegalovirus
HHV-6, HHV-7
HHV-8 (Kaposis sarcoma herpevirus)
 Lymphocytic cell infiltration and elevated CD8,
interferon-gamma, tumour necrosis factor-alpha,
IP-10 and RANTES transcripts were significantly
induced.
Herpes virus persist in the human body by
becoming latent, hiding from immune system in
the cell bodies of neurons.
After primary infection, some people may
experience sporadic episodes of viral reactivation.
 The primary infection, which occurs on initial contact
with the virus, is acquired by inoculation of the
mucosa, skin, and eye with infected secretions. The
virus then travels along the sensory nerve axons and
establishes chronic, latent infection in the sensory
ganglion (such as trigeminal ganglion).
Recurrent HSV results when HSV-1 reactivates at latent
sites and travels centripetally to the mucosa or the
skin, where it is directly cytopathic to epithelial cells,
causing recrudescent HSV infection in the form of
localised vesicles or ulcers.
 Outline of IMMUNE SYSTEM

I. Two arms of the Immune System

A. Innate Immunity
B. Adaptive Immunity

II. Recognition of Pathogens and Effector

Mechanisms
 Two Distinct Arms of the Immune System
Both systems are interrelated
Innate Immune system= general, attacks
pathogens without specificity
- innate refers to the fact that the responses do
not require time to develop, they are ready to go
- can recognize molecular patterns on the
pathogen itself and an infected cell
- most of our encounters with pathogens and
toxins are taken care of by the innate immune
system
 Cells of the Innate Immune System

The main cell types are:

-Macrophages

-Dendritic cells

-Natural killer (NK) cells

 Macrophages

Macrophage means large, eating

Their function is to ingest and eliminate infectious agents,
process and present antigen (pieces of the pathogen)
Help to regulate other immune cells, both innate and
adaptive
 Dendritic Cells

Have a very characteristic shape with long cytoplasmic processes

(dendrites)
Reside in tissues in an immature form, mature when an infection or injury
occurs, induce innate response
Mature DCs can travel to lymphoid organs (lymph nodes, spleen, etc.)
with antigen on their surface and act as antigen-presenting cells (APC),
very effective
Also influence activated T-cells
 Natural Killer (NK) Cells

Responsible for background in experiments

testing the ability of lymphocytes to kill specific
target cells
Large granular lymphocytes that do not need to
be induced or primed to kill cells
 Two Distinct Arms of the Immune System
The Adaptive Immune System=highly specific
If the innate immune response cannot control
and eliminate pathogens it initiates and mediates
the adaptive immune response
adaptive refers to the fact that it takes time to
produce this response
Another difference is that once the pathogen is
cleared, the cells involved can form memory of
the pathogen
If the organism is infected again with the same
pathogen, these cells can mobilize more quickly
to defend the host
 Cells of the Adaptive Immune System

The main cell types are:

- T cells

- B cells
 T cells

T-cells mature in the thymus

Two main phenotypic types of T-cells: CD4+ T cells (T
helper cells) and CD8+ T cells (cytotoxic T cells)
Responsible for specific recognition of antigens and can
retain memory of an antigen
 B cells

Mature in the bone marrow

Produce specific antibodies against invading organisms
Can differentiate into plasma cells (produce antibody)
and retain memory of the antigen encounter
Three Defining Characteristics of the Immune
System
It can discriminate between self and non-self
-between host and non-host

It remembers what it has encountered (memory)

-allows the immune system to react more quickly
and effectively to previous pathogens
-basis for vaccination

Responds only to the pathogen at hand

(specificity)
How does the immune system
achieve these three goals??
Recognition of Pathogens
 Antigen
Substances from a pathogen that can trigger an
immune response
Epitopes: small subregions on the antigen that are
recognized by receptors on immune cells
-also known as antigenic determinants
-one antigen can have many epitopes that can be
recognized
-can be amino acids, sugars, lipids, or nucleotides
Adaptive immunity=recognize highly unique epitopes -
T-cell specific for an epitope of gp150 in HIV
Innate immunity= recognize antigens that are not
species specific, antigens that are common in a class of
microorganism (bacteria, viruses, parasites, etc.)
 Antigen Recognition-Adaptive
Immunity
B and T lymphocytes
Have surface proteins that recognize only one antigen
-very very specific
-surface proteins are called antigen receptors
- it is the antigen receptors that are responsible for the
specificity
- T-cell: one small peptide
- B cell: usually more than just a small peptide needed
Once the antigen binds the receptor, B or T-cell
becomes activated and this triggers an immune
response
CD8+ T-cell CD4+ T-cell
http://thyroid.about.com/library/immune/blimm13.htm
How is the specificity of the receptors
created????
The answer: combine conserved areas of the
receptor (only need a few genes) with highly
variable gene segments created by
recombining DNA, DNA mutations, etc..
Why?? Because there is not enough DNA in a
cell to encode one gene for each possible
antibody
Both B and T cell receptors have the ability to
recognize any antigen that is encountered
 antibody

http://flipper.diff.org/app/items/info/1052
 Differences Between T-cell and B-cell
Receptors
B-cell receptor:
-recognize antigen in native form (as they exist
in nature)
-does not need help from other cells to
recognize the antigen
 T-cell receptor:
-CANNOT recognize native antigen
-can only recognize antigen that has been broken down into
epitope sized peptide fragments
-antigen has to go through antigen processing
-recognizes the peptide and a surface protein on the cell that
carries the peptide
-surface proteins are called major histocompatibility complex
(MHC) proteins
-MHC presents the peptide to the T-cell receptor in a process called
antigen presentation
-T-cells only recognize peptides in the presence of MHC
-Antigen recognition by T-cells is said to be MHC restricted and T
cells must be histocompatible to be activated
Antigen presenting cell (APC)
Macrophages, Dendritic cells,
B cells

T-cell
 MHC Proteins
Highly variable from person to person, most
variable proteins known
Variability is what allows the immune system to
distinguish self from non-self
MHC Class I- expressed on all nucleated cells
MHC Class II-primarily expressed by immune cells
-macrophages, dendritic cells, B cells and T cells
In humans MHC are also called human leukocyte
antigens (HLA)
 MHC proteins contain indentations or clefts that can
accommodate small peptides (8-11 aa for MHC I and
13-17 aa for MHC II)
-the peptides that make up the cleft determine which
antigen peptides can bind there

MHC class I proteins are primary ones responsible for

graft rejection
-must be expressed by target cell to be killed by an
antigen-specific CD8+ T cell

MHC class II- all of the professional antigen

presenting cells express it
-macrophages, B cells, dendritic cells
 (February 2003, www3.ebi.ac.uk/Services/imgt/hla/cgi-
bin/statistics.cgi).

-Peptide binding in the pocket of a MHC-I molecule

 Because of the huge variety, MHC from one individual will
interact differently with antigen than another individual
A protein from a pathogen contains epitopes A, B, C, D
-A person may only present epitope A because of their MHC
type and another person may only present epitope B

C
D
Antigen Recognition-Innate Immunity
Natural Killer (NK) cells play a big role in triggering
innate immunity
-do not have antigen receptors
-have surface receptors that inhibit killing function
-killer inhibitory receptors (KIRs)
-recognize abnormal levels of MHC class I
-if a cell has normal amount of MHC class I then NK
cells do not kill it
-if MHC class I is in lower amounts (some virally
infected cells and tumor cells do this) it will be killed
 Other Innate Cells
Dendritic cells and Macrophages recognize molecules
that are common to groups of pathogens
-antigen receptors are called pattern recognition
receptors (toll-like receptors)
-examples of these molecules are carbohydrates and
lipopolysaccharides, GpC motifs in bacterial DNA (are
not in mammalian DNA)

Kumar: Robbins and Cotran Pathologic Basis of

Disease, Professional Edition , 8th ed.
Copyright 2009 Saunders, An Imprint of Elsevier
What happens after the antigen
is recognized????
Immune Activation and Effector
Mechanisms
 Immune Activation-Adaptive Immune
System
T- and B-cell receptors are anchored in the cell membrane
When the antigen receptor binds antigen then the associated
molecules are altered to activate the lymphocyte

http://bioweb.wku.edu/courses/biol328/TcR.htm
http://www.arthritis.co.za/immunologyupdate.html
Immune Activation-Adaptive Immune
System
The ability of an extracellular antigen to cause
activation of intracellular processes across the
cell membrane requires signal transduction

Usually need more than one signal to do this

Second signal is not antigen specific

 APC

T cell
Immune Activation-Adaptive Immune
System
B and T cells that have been activated then
undergo cell division

Give rise to a clonal expansion of just the cells

specific to that antigen

Called clonal selection and is important for

immune control of the reaction
 T cell clonal expansion

2012 Australian Society for Immunology

T cell clonal expansion
Memory cells

Schluns , et al. 2003

 B cell clonal expansion

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/ClonalSelection.html
 Immune Activation-Innate Immunity

Very similar to T-cell receptor activation

Macrophage signaling NK cell signaling

Current Protocols in Cytometry, 2001

http://biology.nd.edu/people/faculty/schorey/
 Immune Effector Mechanisms
Chain of Events:
1. Pathogen enters the host
2. Innate immune system is first line of defense
-fills lag time and tries lessen pathogens
strength
3. Adaptive immune response is second
-can take several days in a nave host
-low number of specific cells, need to activate
and expand
 Basic Effector Mechanisms
Adaptive Immune Response:
-antibody production
-activating immune cells and getting them ready to directly or
indirectly kill organisms
-actually killing the appropriate cells or organisms
-regulate all of these functions

All done by specific cells with the control of specific cytokines

Innate Immune Response: also controlled by cytokines

 Cytokines
Small proteins that are similar in function to hormones

Control cellular functions over a small distance, in close

proximity to the cell that secreted it-paracrine regulation
-activated helper T cell secretes a cytokine to help
the B cell nearby differentiate into an antibody-
secreting cell

Can also act on the cell that secreted it- autocrine

regulation
-activated T helper cell secretes a cytokine that helps
it to proliferate and clonally expand
http://trialx.com/curebyte/2011/06/30/clinical-trials-and-images-of-cytokines/
 Control of Immune Effector
Mechanisms
Amount and type of cytokine produced
-there are more than 100 cytokines known

Level of expression of cytokine receptors on immune

cells

Different types of cells involved and how quickly they

can respond

Antibodies that can recognize and bind to the antigens

http://www.biocarta.com/pathfiles/h_inflamPathway.asp
How are target cells killed?
 Two Types of T cells
Helper T cells
-Express CD4 on their surface
-produce cytokines that help macrophages kill ingested organisms
-help B cells to differentiate into antibody producing cells
-activate other CD4 cells to expand clonally
-help cytotoxic T cells and NK cells kill target cells
-cells directly infected with HIV
-bind epitopes presented by MHC II

Cytotoxic T cells
-Express CD8 on their surface
-Inhibit other cells or kill them
-bind epitopes presented by MHC I
 Extracellular Immune Effector Mechanisms
Extracellular organisms are protected against by:
- antibodies (B cells) and phagocytic cells
(macrophages)

-antibodies are secreted proteins produced by B

cells

-the antibodies secreted by a particular B cell have

the same specificity as the antibody (receptor) on
the surface of the B cell
 Extracellular Immune Effector Mechanisms
- Antibodies bind to whole antigens in their native forms
-good defense against bacteria that can grow outside
of cells
-neutrophils ingest these bacteria but antibody coating
makes this easier
-they recognize the constant region of antibodies
-Opsonization

- directly interfere with the replication of pathogens

- prevent binding of intracellular pathogens to target
cells (HIV)
Process of Opsonization

(macrophage)
Different Types of Antibodies
 Intracellular Immune Effector Mechanisms
Virus infects cell
Viral proteins are produced
Peptides are carried to cell surface to MHC I
Virus-specific CD8+ T cells can see this
Interaction between MHC I peptide complex and
T-cell receptors
Cell is killed by T cell
This can happen faster than new virus production
This is why all cells express MHC I- serves as
immune surveillance
http://www.ncbi.nlm.nih.gov/bookshelf/b
r.fcgi?book=imm&part=A1062&renderty
pe=figure&id=A1063
Intracellular Immune Effector Mechanisms
 Intracellular Immune Effector Mechanisms

MHC II uses an extracellular pathway as it is

loaded with peptides from antigens ingested
outside of the cell

Used mainly by antigen-presenting cells

(macrophages, dendritic cells)
 Intracellular Immune Effector Mechanisms

Macrophages kill microorganisms they have ingested

-need activation by cytokines to help
-organisms covered in antibody are helpful
 Cytokines of Innate and Adaptive Immune
System
Produced in small quantities and are very short lived

They have many different functions and some are

redundant

They usually bind very tightly to their receptors

Cytokine receptors can bind more than one cytokine

Very important regulators of the immune response

http://www.biocarta.com/pathfiles/h_inflamPathway.asp
Localized infection- an infection that is restricted to a specific location or region
within the body of the host .
Areas affected red, tender, swollen, warm, loss of function.
Usually can be treated at home ( except cases like internal infection like
appendix, heart prompt medical intervention)

Systemic infection- spread through the bloodstream to the entire body, and
shakiness, chills, weakness, nausea, vomiting, and aches in the joints may be felt
For example : Influenza (responds well to home treatment)
Other conditions such as septicemia/ malaria medical attention)
*septicemia Bacteria infect bloodstream can cause a cascade of changes to
damage multiple organ systems, leading to organ failure and death Symptoms
include fever, difficulty breathing, low blood pressure, fast heart rate, and mental
confusion.
Gram negative bacteria that have overcomed
the LDB into systemic circulation
sensed by TLR4 express non-
haematopoietic cells thru regconition of PAMPs
emergency state

TLR4 signals transduction in non-H cells occurs

in a MYD88 manner expression and secretion
of large quantities of G-CSFR

In the Bone Marrow

N-H cell-derived G-CSF acts on multiple levels
of granulocytic lineage as G-CSFR is expressed
continuously from early haematopoetic steam
& progenitor cell stage to mature neutrophil
stage (anti-apoptic & microbicidal effect)
-GCSF- stimulates neutrophil mobilization
through inhibition of CXCR-4,CXCL12
-promotes myeloid progenitor proliferation &
granulocytic differentiation enhanced
generation of neutrophils & neutrophil output
into circulation to site of infection- resolve
infection
Expansion of granulopoiesis,lymphopoiesis &
monocytopoiesis are decreased