Immunology

Mechanisms of Wound Healing

and Hypersensitivity
 Our Immune system….

 …can help heal our pets

 …can protect our pets

 BUT it can also

malfunction and …..
cause disease
Our Immune system
Tissue Cells
Blood Cells
 Innate Immunity
 Fast
 Born with it
 Always Ready
 All Pathogens treated
 equally
 No Memory

Tissue at site of
infection
 Innate immunity
– important for wound healing
 Wound Healing - Stages

1) Inflammation 2) Proliferation, Migration 3) Resolution

Contraction
 Initial Inflammatory Phase
• Cytokines and other
inflammatory mediators
released

• Growth factors released

• Clotting elements arrive from

blood

• Haemostasis

• Fibrin Clot formation

 Initial Inflammatory Phase
• Damaged blood vessels activate platelets which together with fibrin
and platelet aggregation form the blood clot.
• The clot acts as a environment in which growth factors can work
and cells can migrate and move about. “the Matrix”
• Serum, the fluid component of the clot also contains various growth
factors.
• Leukocytes, mainly neutrophils passively leak into the damaged
tissue and clot.
• Also there is rapid activation of immune cells already present in the
damaged tissue, Mast cells, T lymphocytes and Dendritic cells
• These cells release a rapid pulses of chemokines and cytokines
 Initial Inflammatory Phase
• These chemical signals attract and
recruit circulating neutrophils, and
monocytes from nearby blood
vessels and begin a organized
process to cause the migration of
inflammatory cells to exit the blood
vessels and migrate to the injury
site.

• This process is enhanced by mast

cells releasing nitric oxide,
histamines and other factors,
causing dilation and increased
permeability of blood vessels
Initial Inflammatory Phase – The Matrix
Initial Inflammatory Phase – The
Matrix
 Initial Inflammatory Phase
• Neutrophils are activated within minutes
• They have an important role in killing invading micro organisims
• They are also involved in promoting resolution of the clot,
angiogenisis (growth of blood vessels), and epithelialisation.
• Monocytes are drawn into the wound later, maximum numbers
occur at approximately 24 hours
• They mature into macrophages, start phagocytosis matrix, cell
debris and spent neutrophils as well as their various roles in
fighting micro organisms.
Initial Inflammatory Phase
 Proliferation, Migration and Contraction
• The clot and scab form quickly and restore the protective
barrier if the skin

• These next phases of wound healing effect a more permanent

skin closure

• The speed of this process depends on:

-size of wound
-age and health of tissue

• Proliferation of granulation tissue (stroma cells) gradually

replaces the clot matrix and provides a bed for
epithelialization to occur
Proliferation, Migration and Contraction
Proliferation, Migration and Contraction

Epithelialization is
the most important
part of this process
as it restores the
skin barrier
Proliferation, Migration and Contraction
-Epithelialization
 Proliferation, Migration and Contraction
- Angiogenesis
• Angiogenic Cytokines released
from damaged tissue stimulate
endothelial cells to proliferate and
migrate

• New capillary beds form

• Angiogensis is vital to be able to

complete the final stages of wound
healing

• Wound dressings that disturb the

matrix can delay both angiogenesis
and epithelialization Ulcers
Poor Wound Healing - Wound Ulcer
 Proliferation, Migration and Contraction

• Fibrin + Fibroblasts + Myofibroblasts + Collagen fibers

form the SCAR TISSUE

• This phase takes days to weeks

 Proliferation, Migration and Contraction
Fibrin Collagen Fibers

Contraction

• Once scar tissue forms it can contract and greatly reduce the
size of the wound.
 Resolution
• During this phase of wound healing the skin is restored to
normal function and appearance as much as possible.

• However hair follicles and sebaceous glands do not

generally develop in the scar tissue.

• Blood vessels are refined, the tissue stroma is remodeled

• Unwanted tissue and inflammatory cells undergo

apoptosis and phagocytosis by macrophages

• Also the inflammatory response in switched off by

anti-inflammatory mediators.
Resolution
 Resolution
• If resolution is not well regulated
hyper-proliferation can result.
Often called ‘proud flesh’
 Primary Wound Healing

Hemostasis
Platelets Fibrin clot formation,
Vasoactive substances, Cytokine and growth factor release
Inflammation
Tissue Cells Platelet activating mediator release,
Vasoactive substances Cytokines and Chemokines release
Neutrophils and Migration to wound, further mediate inflammation.
Monocytes Killing, phagocytosis and wound debridement
Macrophages Migration to wound, Inflammation, Killing, Phagocytosis,
More Cytokines and Growth factors released

Proliferation, Migration, Contraction

Skin Barrier Restoration
Keratinocytes Epithelialization
Dermis Restoration
Endothelial Cells Angiogenesis
Fibroblasts Become dermal fibroblasts - Fibroplasia

Keratinocytes Epidermis remodeling

Myofibroblasts Wound Contraction
Apoptosis and scar maturation
Endothelial Cells Apoptosis and scar maturation
 Wound Healing
 1) Wounds heal best in a moist environment
 2) Moist wound bed allows epithelial cells, and many other cell
types and growth factors to migrate into healing wound
 3) Foreign material, necrotic tissue, and bacteria delay or stop
wound healing
 4) Excessive exudate needs to be removed from wound for optimal
healing
 5) Also for optimal healing, wounds need physical protection, also
maintainance of body temperture and pH
 6) Need adequate blood supply to provide all the necessary
elements of healing wound
First Intention
Wound Healing
 Surgery wounds or
small wounds
 Heal quick
 Little tissue loss
 Little granulation
tissue required
 Second and Tertiary
Wound Healing
 Open wounds that can not be closed
 Slower to heal
 Tissue loss
 Lots of GRANULATION TISSUE
 Prone to secondary infection
 Require more intensive treatment and
care
 Wound healing can become delayed,
or if problems form a CHRONIC
WOUND (or Ulcer)
 Wound Healing Process
Granulation +
Clean Wound
Epithelialization
Make the Wound a Nice Place For
The Immune System Cells to Live
Use Dressings That Keep Wound
Moist and Clean
 Look After The Patients Immune
System
 Keep Hydrated
 Keep Clean
 Keep well fed
 And.............
Hypersensitivity
Adaptive Immunity
 The Basics
- Adaptive Immunity
 Humoral (Antibody)  Cell Mediated Immunity
Mediated Immunity

 T Lymphocytes
 B Lymphocytes
 Direct cell to cell
 Uses Antibody which
circulates in serum communication (cytokines)
 Main defense against  Main defense against
extracellular pathogens intracellular pathogens
  Also fight against tumor
antigens
 Adaptive Immunity
 Slow to get going

 Pathogen specific

 Has Memory

 Activated in immune

 organ (lymph node)

 Make tools to rapidly

Lymphoid Tissue
 kill specific pathogen
Problems - Hypersensitvity
 Immune Disorders

-The Adaptive Immunity can over - react

Ahh
Rheumatoid
Arthritis
Hypersensitivity
Type 1 Hypersensitivity
 Immunoglobulin E - IgE
 Has similar structure to IgG

 Does not cross placenta

 Produced in lining of
respiratory and intestinal
tracts

 Mediates hypersensitivity
reaction

 Responsible for anaphylactic

shock and allergic response

 Plays a role in immunity

against helminthic parasite
 (e.g. lungworm, roundworms)
 Type I hypersensitivity reaction
- Allergy
•Type-I hypersensitivity reaction is mediated by IgE.

•It is induced by certain types of antigen called allergens

such as pollen grains, dandruff, dusts, food components etc.

•Allergens induces humoral antibody response.

•This IgE class of antibodies have high binding affinity to Fc

receptor on the surface of tissue mast cells and blood
basophils. Mast cells and basophils bound by IgE are said to
be sensitized.

•A latter exposure to the same allergens sensitized mast

cell and basophils causing degranulation of these cells.
Type 1 Hypersensitivity
 Type I hypersensitivity reaction:
-Allergy
• Degranulation causes release of pharmacological active
mediators (chemicals such as histamine, heparin, serotonin,
cytokines, leukotriene, prostaglandin etc. )

• These chemicals act on surrounding tissue causing

vasodilation and smooth muscle contraction as well as
other visible symptoms such as mucus production,
sneezing, etc.

• This effect is also termed as Allergy.

• The allergic reaction may be localized or systemic

(Anaphyaxis) depending upon types of allergen.
 Type II hypersensitivity reaction:
-Antibody Mediated Cell Destruction
• Type II hypersensitivity reaction involves antibody mediated
destruction of cells. It is also known as cytotoxic reaction.

• In this hypersensitivity reaction, specific antibody (IgG or IgM)

bound to cell surface antigen and destroy the cell. If the cell is
microorganism, killing of cell is beneficial to host. However in
Type II hypersensitivity, the cells are own RBC.

• The killing of cell can occurs by 2 mechanisms.

1) Complement mediated cell lysis
2) Antibody dependent cell mediated cytotoxicity (ADCC)
Immunoglobulin G - IgG
 Immunoglobulin M - IgM
 Accounts for 5-10% of serum
proteins

 Mostly present in blood

 Can not cross placenta

 Half life 5 days

 Agglutinates (Clumps
together) bacteria

 Activates Complement
Pathway

 Responsible for protection

against blood borne
 a) Complement mediated lysis of cell:
(e.g. blood transfusion reactions)
•Complement system is a system of
lytic enzyme which are usually inactive
in blood.

•Enzymes of complement system are

activated by antigen-antibody
complex.

•When antibody binds to antigen

(microorganism or RBC) they form Ag-
ab complex. Complement
•Ag-ab complex can activate
complement system on the surface of
cell (RBC) it causes lysis of cell.
b) Antibody dependent cell mediated
cytotoxicity. (ADCC)
• Antibody (IgG, IgM) binds with antigen
on a target cell and to a T Cell with a
Fc receptor

• Most cytotoxic cells contain digestive

enzymes.

• These enzymes are released on the

surface of target cell killing them.
The antibody itself does not kill the
cell but mediates killing by presenting
antigen to cytotoxic cell.

• The cytotoxic cell depends on the

antibody to bind antigen.
Type II hypersensitivity reaction:
-Antibody Mediated Cell Destruction
 Type III hypersensitivity reaction:
-immune complex formation
• The reaction of antibody with antigen
generates immune complex.

• In most of the cases, these immune

complexes are removed from blood
circulation and destroyed

• BUT In some cases large amount of

immune complexes are formed and
deposited on various body parts.

• This can cause activation compliment

and attract neutrophils to the site
 Type III hypersensitivity reaction:
-immune complex formation
•immune complexes are
deposited on basement
membrane, neutrophils
releases lytic enzymes
to destroy immune
complex.
•The lytic enzymes cause
damage to tissue
surrounding of immune
complex deposits

•C5a,C3b are important

compliment system
mediators Basement Membrane
Type III hypersensitivity reaction:
- immune complex formation

Systemic Lupus Erythematous

-often occurs at muco-cutaneous junction (where skin meets
mucous membrane)

Rhuematoid Arthritis
- Usually multiple joints, sudden
onset

Glomerulanephritis
 Type IV hypersensitivity reaction
- cell mediated hypersensitivity
•Type IV hypersensitivity reaction is
also known as delayed type
hypersensitivity (DTH).
•When some sensitized T helper cells
encounters an antigen again , they
secrete cytokines that can cause
influxes of cytotoxic T cells and
activated macrophages.

•DTH occurs slowly and reaches a

peak level within 48-72 hours after
2nd encounter of antigen.
 Type IV hypersensitivity reaction
- cell mediated hypersensitivity
•Activated macrophages
releases lytic enzymes that
damage surrounding tissues

•leads to non-specific
destruction of tissues and
intracellular pathogens.

•Generally pathogens are

killed rapidly with little tissue
damage.

•However in some case,

chronic inflammation
develops into a visible
granulomatous reaction.
 Type IV hypersensitivity reaction
- cell mediated hypersensitivity

• Diabetes Mellitus Type 1

• Contact
Dermatitis
• Lick Granuloma
?