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1

What does immunology have to do with oral biology and dentistry?

The body’s natural immune response is the primary mechanism for fighting bacterial, viral, fungal, and parasitic infections, and for protecting us from cancer.

____ can aid the body by reducing or eliminating some types of infection, and they can let the immune response function more ____. 

Knowing how these work is essential to providing effective health care.

In some situations, a ____ immune response may cause ___ ____(_____) or may be directed to the ___ ____ themselves (____). This is an undesirable situation that needs to be remedied if possible.

We live in a time when treatments of medical issues are complex, many of which directly affect the immune response. 

Examples:

Patients undergoing ___ treatment

Tissue or organ ____

Treatment of ____ disorders (e.g., Crohn’s disease, rheumatoid arthritis, SLE).

It is important that dentists understand how those disorders are treated, and how dental care might impact that.

  

 

 

 

What does immunology have to do with oral biology and dentistry?

The body’s natural immune response is the primary mechanism for fighting bacterial, viral, fungal, and parasitic infections, and for protecting us from cancer.

Antibiotics can aid the body by reducing or eliminating some types of infection, and they can let the immune response function more efficiently. 

Knowing how these work is essential to providing effective health care.

In some situations, a hyperactive immune response may cause tissue damage (immunopathology) or may be directed to the body’s tissues themselves (autoimmunity). This is an undesirable situation that needs to be remedied if possible.

We live in a time when treatments of medical issues are complex, many of which directly affect the immune response. 

Examples:

Patients undergoing cancer treatment

Tissue or organ transplantation

Treatment of autoimmune disorders (e.g., Crohn’s disease, rheumatoid arthritis, SLE).

It is important that dentists understand how those disorders are treated, and how dental care might impact that.

  

 

 

 

2

The Immune System

What?

It is a____ system composed of multiple ___, ___, and ___ that interact to protect the body from ___ and ___.

Where?

In nearly __ ___of the body, with the exception only of the ____ and the ___ ___ ___

  • Brain has its own protection

Localized in ____ _____ _____- the ___ tissues.

 

 

The Immune System

 

What?

It is a physiological system composed of multiple cells, tissues, and organs that interact to protect the body from infection and disease.

 

Where?

In nearly all tissues of the body, with the exception only of the brain and the central nervous system.

Brain has its own protection

Localized in specialized immunological compartments - the lymphoid tissues.

 

 

3

Immunity requires a balance in the immune response in ____ and ____

Health: Immune system ___ you from disease and infection

Disease: Immune system is __ ___

Allergy, immunodeficiency, transplant rejection, autoimmune disease

Immunity requires a balance in the immune response in health and disease

Health: Immune system protects you from disease and infection

Disease: Immune system is hurting you

Allergy, immunodeficiency, transplant rejection, autoimmune disease

4

CD (___ of ____) markers

  • Molecules on cells that ___ ____ ____ ____of the immune system.
  • More than ___ different CD markers now identified (the number is still growing).
  • _____ expressed on cells of the immune system.
    • A few expressed on ___ cells
    • Most are___ expressed, e.g., CD4 (_____), CD8 (____), CD19 (___), CD14 (____).
  • Extremely useful to immunologists and clinicians for ____ lymphoid cell populations.
    • To know which groups of cells are present
    • For example, the human CD4:CD8 ratio is normally about ____
      •  In AIDS because of the loss of ___ cells, the ratio drops to ___than 2.0 as the number of CD4+ T cells declines (e.g., 1.0, 0.8, 0.6, 0.4, etc).

CD (Cluster of Differentiation) markers

Molecules on cells that define specific cell populations of the immune system.

More than 350 different CD markers now identified (the number is still growing).

Differentially expressed on cells of the immune system.

 A few expressed on all cells

 Most are selectively expressed, e.g., CD4 (T helper cell), CD8 (T cytotoxic cell), CD19 (B cells), CD14 (macrophages).

Extremely useful to immunologists and clinicians for identifying lymphoid cell populations.

To know which groups of cells are present

For example, the human CD4:CD8 ratio is normally about 2:1 (or 2.0).

 In AIDS because of the loss of CD4+ cells, the ratio drops to less than 2.0 as the number of CD4+ T cells declines (e.g., 1.0, 0.8, 0.6, 0.4, etc).

 

5

Antigen vs. Immunogen

Antigen (Ag):  Any substance that ___ with a cell of the immune system (can be ___ or “__” Ag).

Self Ag involved in autoimmunity

 

Immunogen: An ___ that induces an ___ ____; not all ___ are ____

You can have something recognized by the immune system that doesn’t induce a response 

Antigen vs. Immunogen

Antigen (Ag):  Any substance that reacts with a cell of the immune system (can be foreign or “self” Ag).

Self Ag involved in autoimmunity

 

Immunogen: An antigen that induces an immune response; not all antigens are immunogens.

You can have something recognized by the immune system that doesn’t induce a response 

6

Primary and Secondary Lymphoid tissues

  • Primary Lymphoid tissues  (also called ‘___ Immune System)
    •  The site of immune system__ ___
    • ___ ___
    • _____
  • Secondary Lymphoid tissues (also called ‘____ Immune System)
    • ___ ____ other than ____ lymphoid tissues (s___, b___, l___ ____, a___, t___, a___, P____’s patches in intestines, etc.)
    • ___ ___ of the immune system.
    • This is where immune response is ___ and ____

Primary and Secondary Lymphoid tissues

Primary Lymphoid tissues  (also called ‘Central Immune System)

 The site of immune system cell development

 Bone marrow

 Thymus

This is where immune system develops

Secondary Lymphoid tissues (also called ‘Peripheral Immune System)

 All tissues other than primary lymphoid tissues (spleen, blood, lymph nodes, adenoids, tonsils, appendix, Peyer’s patches in intestines, etc.)

Work place of the immune system.

This is where immune response is generated and maintained

 

 

 

7

Blood-Lymph Circulation

  • Two mechanisms for movement of cells throughout the body.
    • The ____ action of the ___ moves cells through the ___
    • ____ ____ deposit and retrieve cells passively ____ of tissues.
    • Cells in the lymphatic vessels are ____ to the _____
    • They relate to each other.
  • Infection in foot. Infectious material makes its way to a lymph node.
    • Cells of immune system would move thru lymph node
    • Those cells dumped back into circulation after tissue
    • From the circulation, they come down into lymph node
  • Both systems feed___ of the ___ ___ through the___ ___

Blood-Lymph Circulation

Two mechanisms for movement of cells throughout the body.

The pumping action of the heart moves cells through the circulation.

Lymphatic vessels deposit and retrieve cells passively in/out of tissues.

Cells in the lymphatic vessels are returned to the circulation. 

They relate to each other.

Infection in foot. Infectious material makes its way to a lymph node.

Cells of immune system would move thru lymph node

Those cells dumped back into circulation after tissue

From the circulation, they come down into lymph node

Both systems feed cells of the immune system through the lymph nodes.

 

 

8

Lymph Nodes in the Jaw and Neck

More than ___ lymph nodes in the jaw/neck region alone and at least ___ in the body overall

Each one of these lymph nodes is a station where the immune response will be ____

Immune response ___ in lymph node and then cells are sent out to the ___ of ___

Regional/Draining lymph nodes: ______________

Lymph Nodes in the Jaw and Neck

More than 50 lymph nodes in the jaw/neck region alone and at least 120 in the body overall

Each one of these lymph nodes is a station where the immune response will be generated

Immune response starts in lymph node and then cells are sent out to the area of infection

Regional/Draining lymph nodes: Ones close to infection

9

Four ways leukocytes enter and leave a lymph node

1.Enter from the ____ via the ___ ___ ___

2.Return to ___ via the ___ ___ ____

3.Enter from the____  via the ____ ___ ____

4.Return to the ____ via the ___ ___ ___.

 

 

Four ways leukocytes enter and leave a lymph node

1.Enter from the circulation via the lymph node artery

2.Return to circulation via the lymph node vein.

3.Enter from the lymphatics via the afferent lymphatic vessel.

4.Return to the lymphatics via the efferent lymphatic vessel.

 

 

10

Structural Organization of a Lymph Node

  • Lymph nodes are areas where ____ (T cells and B cells), ____, _____ cells, or ____ cell, and____ (Ag) come together to_____ an immune response.
  • This occurs in ____ ___ within the lymph node. 
    • Lymph nodes are ______.
    • Well cells of immune system are fed into lymph node they go and find their own compartment
    • Areas for B cells, T cells, macrophages
    • If Ag is brought in with these 3 cells then the immune fcn takes place

Structural Organization of a Lymph Node

Lymph nodes are areas where lymphocytes (T cells and B cells), macrophages, dendritic cells, or Langerhans cell, and antigen (Ag) come together to initiate an immune response.

 This occurs in specialized regions within the lymph node. 

Lymph nodes are compartmentalized.

Well cells of immune system are fed into lymph node they go and find their own compartment

Areas for B cells, T cells, macrophages

If Ag is brought in with these 3 cells then the immune fcn takes place

 

11

The Spleen

  • An organ with some_____properties.
    • Not _____ a lymphoid organ
  • It has many more _____ than the lymph nodes.
  • Acts as a ___ for the ___ to remove ___ ___
  • It has numerous ____ located in the ‘___ ___’.
  • Red pulp: ___
  • White pulp: ___

The Spleen

An organ with some immunological properties.

Not exclusively a lymphoid organ

It has many more RBCs than the lymph nodes.

Acts as a filter for the blood to remove dying RBCs.

It has numerous leukocytes located in the ‘white pulp’.

Red pulp: RBC

White pulp: WBC

 

12

Hematopoietic vs. Leukocyte 

Hematopoietic cells are ___ of the ___ ___ – the ___ (the white blood cells), the ____ and ____ (cells involved in ____), and the ____(red blood cells).

Leukocyte refers only to the ___ blood cells, the cells of the ___ ___

 

Hematopoietic vs. Leukocyte 

Hematopoietic cells are all of the blood cells – the leukocytes (the white blood cells), the megakaryocytes and platelets (cells involved in clotting), and the erythrocytes (red blood cells).

Leukocyte refers only to the white blood cells, the cells of the immune system.

 

13

Leukocytes

  • ____ (____ cells)
    • ___
    • ___
  • ____ (___ cell)
    • B
    • E
    • N____= G_____
    • M____ (precursor of _____)
    • M____
  • And…
    • __ ___
      •  ___
      • ___
        • We really don’t know what they doing
    • ____ cells
    • ____ cells     

Leukocytes

Lymphocytes (lymphoid cells)

T cells= T lymphocyte

B cells= B lymphocyte

Myelocytes (myeloid cells)

Basophils

Eosinophils

Neutrophils= Granulocyte

Monocytes (precursor of macrophages)

Macrophages

And…Mast cells (tissue and mucosal mast cells)

We really don’t know what they doing

Dendritic cells

Langerhans cells     

 

14

Hematopoiesis (aka hemopoiesis)

  • Process of ___ the ____,  the cells of the immune system for our purposes.
  • Takes place in the ___ ____
  • Bone marrow provides:
    • ___ ____ (stromal cells)
    • ___ ___ for development
    • ____ ___ ___ cells.  
      • A cell that is the source of all cells of the immune system.
  •  

Hematopoiesis (aka hemopoiesis)

Process of generating the blood cells, the cells of the immune system for our purposes.

Takes place in the bone marrow.

Bone marrow provides:

Structural support (stromal cells)

Growth factors for development

Hematopoietic pluripotent stem cells.  

A cell that is the source of all cells of the immune system.

 

15

Bone marrow pluripotent stems cells give rise to all leukocytes (and erythrocytes)

Pluripotent stem cells:

  • A __ ____ cell population
  • Some become __ __ ___
  • Some ____ into a cell of the ___ ___
  • Each stem cell will become ___ (and __ ___) type of cell of the immune system.
  • Thus, all cells of the immune system arise from a ___ ___ ___

 

Bone marrow pluripotent stems cells give rise to all leukocytes (and erythrocytes)

Pluripotent stem cells:

 A self-renewing cell population

 Some become new stem cells.

 Some differentiate into a cell of the immune system.

 Each stem cell will become one (and only one) type of cell of the immune system.

 Thus, all cells of the immune system arise from a pluripotent stem cell.

 

16

____ bone marrow transplantation

  1. Collect patient’s ___ cells from their __ ___using a___ -activated cell ___
  2. ____ patient to destroy __ ___ (the source of the leukemia).
  3. Inject patient’s __ ___ __ back to ____the immune system.
  4. There is no need for _____ drugs or tissue matching to prevent failure of the bone marrow graft. 

Autologous bone marrow transplantation

Collect patient’s stem cells from their bone marrow using a fluorescent-activated cell sorter.

Irradiate patient to destroy bone marrow (the source of the leukemia).

Inject patient’s healthy stem cells back to regenerate the immune system.

There is no need for immunosuppressive drugs or tissue matching to prevent failure of the bone marrow graft. 

 

 

 

 

17

 Clinical relevance:  A ‘Differential Count’ is a calculation of the___  number (____) of each of the ___ major types of ___ in the circulation.

During bacterial and many fungal infections, ____ counts go up (can approach 80-90%).  During viral infections,_____ counts go up (60-70%).  This provides immediate insight into whether the patient has a viral vs. a non-viral infection.

 

 Clinical relevance:  A ‘Differential Count’ is a calculation of the relative number (percentage) of each of the five major types of leukocytes in the circulation.

During bacterial and many fungal infections, neutrophil counts go up (can approach 80-90%).  During viral infections, lymphocyte counts go up (60-70%).  This provides immediate insight into whether the patient has a viral vs. a non-viral infection.

 

18

Immunity

  • Innate
    • ___
    • ____
  • Adaptive

    • ____

    • ___

  • Specificity:    Response is ____ to a ___ ___
  • Ag Memory: ____ to the same antigen leads to a ___ and more___ response.  
  •  
  •  

Immunity

Innate

Ag Non-Specific

No Memory

  • Adaptive

    • Ag Specific

    • Memory

Specificity:    Response is restricted to a single antigen.

Ag Memory: Re-exposure to the same antigen leads to a stronger and more rapid response.  

 

 

19

Innate Immunity

  • Cells
    • ___, ___, ___, ___ cells, ___ cells
    • Cells that release ____ ____(___, ____, ___cells)
  • Toll-like receptors          
    • Key elements in the ____ of cells of ___ immunity

Adaptive Immunity

  • Cells
    • ____
    • ____
    • ____ cells (B cells that produce ___ levels of ___)
      • Plasma cells are terminally differentiated B cells
    • All are antigen-___

There is collaboration bw two types of immunity

Innate Immunity

Cells

Neutrophils, monocytes, macrophages, dendritic cells, Langerhans cells

Cells that release inflammatory mediators (eosinophils, basophils, mast cells)

Toll-like receptors          

Key elements in the activation of cells of innate immunity

Adaptive Immunity

Cells

T lymphocytes

B lymphocytes

Plasma cells (B cells that produce high levels of Ab)

Plasma cells are terminally differentiated B cells

All are antigen-specific

There is collaboration bw two types of immunity

 

 

 

 

 

20

Four broad types of innate immunity

  • _____ Barriers (e.g., ___, ___ _____ of stomach)
  • ____ Barriers (e.g., ___, __ __ of intestine, __ __, ___)
  • ___ Barriers (___ of ___ molecules); ____ (engulfment of ___ ___)
  • ____ Barriers (___, cells of the ___ ___, ___)

Four broad types of innate immunity

Physiological Barriers (e.g., fever, low pH of stomach)

Anatomical Barriers (e.g., skin, tight junctions of intestine, mucosal membranes, saliva)

Endocytic Barriers (engulfment of small molecules); Phagocytosis (engulfment of particular antigen)

Inflammatory Barriers (edema, cells of the immune system, complement)

 

21

Cells of Innate Immune System and FCNS

Neutrophils: ___ and _______

Monocytes: ___ and ________

Macrophages: ___ and ___________

Dendritic cells and Langerhans cells: ____ and _________

 

Cells of Innate Immune System and FCNS

Neutrophils: phagocytosis and production of immunological mediators

Monocytes: phagocytosis and production of immunological mediators

Macrophages: phagocytosis and antigen-presentation to lymphocytes

Dendritic cells and Langerhans cells: phagocytosis and antigen-presentation to lymphocytes

 

22

What is innate immunity?

Antigen non-specific defense that is used ____or within several ____of exposure to ____. 

Already___ (i.e., does not require ___ to be____). Thus, it is the ___ response of the body to eliminate infectious organisms.

Universally____ first-line-of-defense against infection.

Evolutionarily,___ the adaptive immune response.

Found in ___ ____ organisms.

Uses ____ and ___ that are ancient in their lineage.

Must provide protection against a ___ ___ of pathogens

Defects in innate immunity are very ___ but tend to be __

 

What is innate immunity?

Antigen non-specific defense that is used immediately or within several hours of exposure to antigen. 

 Already present (i.e., does not require time to be generated). Thus, it is the first response of the body to eliminate infectious organisms.

 Universally conserved first-line-of-defense against infection.

Evolutionarily, predates the adaptive immune response.

Found in all multicellular organisms.

Uses receptors and cells that are ancient in their lineage.

Must provide protection against a wide variety of pathogens

Defects in innate immunity are very rare but tend to be lethal.

 

23

Misconceptions about Innate Immunity

Innate immune system is an evolutionary rudiment whose only function is to ___the infection until the ___ immune response is activated.

Adaptive immunity developed because of the____ of the innate immune response.

Innate immune system cannot cope with the __ ___ ___ and extreme  ____ of pathogenic organisms.

All of these are ___ __

 

Misconceptions about Innate Immunity

Innate immune system is an evolutionary rudiment whose only function is to contain the infection until the “real” immune response is activated.

Adaptive immunity developed because of the inflexibility of the innate immune response.

Innate immune system cannot cope with the high mutational rate and extreme  heterogeneity of pathogenic organisms.

All of these are not true.

 

24

Toll-Like Receptors (TLRs)

Until recently, the specific mechanisms involved in innate immune system activation were poorly understood.

___, a surface receptor on ____, was believed to be the primary mechanism of cell activation by ___ ___ such as lipopolysaccharide (LPS).

Our understanding of this has been greatly expanded with the discovery of toll-like receptors (TLRs).

TLRs are molecules on cells of the innate immune system that ___ ___ ___

 

Toll-Like Receptors (TLRs)

Until recently, the specific mechanisms involved in innate immune system activation were poorly understood.

CD14, a surface receptor on macrophages, was believed to be the primary mechanism of cell activation by bacterial products such as lipopolysaccharide (LPS).

Our understanding of this has been greatly expanded with the discovery of toll-like receptors (TLRs).

TLRs are molecules on cells of the innate immune system that recognize foreign antigens.

 

25

How do TLRs Work?

TLRs recognize ___ ___ ____ ___ shared by many different infectious agents (__ __ ___ ___).

The structures recognized by the innate immune system are referred to as ___ ___ ___ ___ (PAMPs).  

The receptors for PAMPs are referred to as ___ ___ ____ (PRRs), i.e., TLRs.  They are ___ on ___ of the innate immune system. 

There is an immediate opportunity for the innate immune system to respond to a wide spectrum of infectious agents.   

 

How do TLRs Work?

TLRs recognize highly conserved molecular structures shared by many different infectious agents (virus, bacteria, fungi, protozoa).

The structures recognized by the innate immune system are referred to as Pathogen-Associated Molecular Patterns (PAMPs).  

The receptors for PAMPs are referred to as Pattern-Recognition Receptors (PRRs), i.e., TLRs.  They are expressed on cells of the innate immune system. 

There is an immediate opportunity for the innate immune system to respond to a wide spectrum of infectious agents.   

 

26

Pathogen-Associated Molecular Patterns (PAMPs) Recognized by TLRs

L______ (LPS from the gram___ ___ ___)

P____ (gram-positive and gram-negative __ ___)

L____ ___ (gram___ ___ ___)

M___-rich ____ (___ but not___ glycoproteins  and glycolipids)

F___ (bacterial flagella)

P___ (bacterial pili)

Bacterial __ ___(high frequency of____ ___ ___ dinucleotide sequences in ____but not ____ DNA)

N_______ (an amino acid common to ___ proteins)

___-stranded RNA (unique to many___)

G____ and z___ (___ and ___ cell walls)

P____and other ___ (microbial ___)

 

 

Pathogen-Associated Molecular Patterns (PAMPs) Recognized by TLRs

Lipopolysaccharides (LPS from the gram-negative cell wall)

Peptidoglycans (gram-positive and gram-negative cell walls)

Lipoteichoic acids (gram-positive cell wall)

Mannose-rich glycans (microbial but not human glycoproteins  and glycolipids)

Flagellin (bacterial flagella)

Pilin (bacterial pili)

Bacterial nucleic acid (high frequency of unmethylated cytosine-guanine dinucleotide sequences in bacterial but not mammalian DNA)

N-formylmethionine (an amino acid common to bacterial proteins)

Double-stranded RNA (unique to many viruses)

Glycolipids and zymosan (yeast and fungal cell walls)

Phosphorylcholine and other lipids (microbial membranes)

 

 

27

There are about 12 TLR

TLR 1 and 2 work together as a ___

Several Different TLRs may be expressed on a Cell of the Innate Immune System

TLRs use very ___ receptors (approximately __ in all) to recognize antigens distributed across many types of infectious agents.

For example, a particular TLR that is specific for bacterial LPS will recognize LPS regardless of the type of bacteria that expresses it (E. coli, salmonella, etc.). 

This, therefore, is a very efficient way for the cells of the innate immune system to operate.  

 

 

There are about 12 TLR

TLR 1 and 2 work together as a dimer

Several Different TLRs may be expressed on a Cell of the Innate Immune System

TLRs use very few receptors (approximately 13 in all) to recognize antigens distributed across many types of infectious agents.

For example, a particular TLR that is specific for bacterial LPS will recognize LPS regardless of the type of bacteria that expresses it (E. coli, salmonella, etc.). 

This, therefore, is a very efficient way for the cells of the innate immune system to operate.  

 

28

____ Pathogen-Associated Molecular Patterns (PAMPs) can be recognized by ________ Expressed on Cells of the Innate Immune System

 

Note: the same PRR (TLR) may  bind to products of___ microbial or viral agents provided they express the same ___

 

Multiple Pathogen-Associated Molecular Patterns (PAMPs) can be recognized by Pattern Recognition Receptors (PRRs) Expressed on Cells of the Innate Immune System

 

Note: the same PRR (TLR) may  bind to products of different microbial or viral agents provided they express the same PAMP.

29

Once the TLR is triggered, what does it do?

TLRs transmit a ___to the innate immune cell's ___ to activate ____ for the synthesis of immune response ____ ____ (_____)

___ , ____ and ____responses are initiated.

TLRs that recognize viral components induce the synthesis of ____, which blocks viral ____ in infected host cells.

 

Once the TLR is triggered, what does it do?

TLRs transmit a signal to the innate immune cell's nucleus to activate genes for the synthesis of immune response regulatory molecules (cytokines).

Inflammation, fever, phagocytosis responses are initiated.

TLRs that recognize viral components induce the synthesis of interferon, which blocks viral replication in infected host cells.

 

30

How TLRs Drive an Inflammatory Response in Oral Tissues

Rapid (___ hrs) secretion of _____ ____ from ___, ___ cells, ____cells, and ____.

IL-1b

TNFa

IL-6

IL-12

 

How TLRs Drive an Inflammatory Response in Oral Tissues

Rapid (4-24 hrs) secretion of proinflammatory cytokines from macrophages, dendritic cells, Langerhans cells, and neutrophils.

IL-1b

TNFa

IL-6

IL-12