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94 Cards in this Set

  • Front
  • Back
Regeneration
structural and functional
`` restitution of
`` `` injured tissue
Repair by scar formation and fibrosis –
repair of injured tissue by
`` fibrous connective tissue

Scarring/fibrosis restores
`` structure/continuity
`` but not
`` `` function of injured tissue
The goal of the repair process is to
restore the tissue to its
`` original state with
`` `` complete restitution of
`` `` `` structure and
`` `` `` function
`` `` `` (regeneration)
When restitution of parenchymal mass cannot occur,
the injured tissues are
`` `` “welded” together by
`` `` `` fibrous connective tissue
`` `` `` (scarring/fibrosis
Regeneration

Urodele amphibians such as newts can regenerate their tails, limbs, lens, retina, jaws and even a large portion of the heart

This remarkable regenerative capacity has been attributed to two main factors:
the capacity of
`` quiescent cells such as
`` `` cardiac myotubes
`` to reenter the cell cycle,

efficient differentiation of
`` `` stem cells
`` in the area of injury

Such capacity for regeneration of
`` whole tissues and organs
`` `` has been
`` lost in mammals
Regeneration

The inadequacy of true organ regeneration in mammals has been attributed to
the rapid
`` `` fibroproliferative response
`` `` and scar formation after wounding
Regeneration

The regenerative capacities of mammalian tissues are
quite variable;
`` in general,
`` `` the more specialized the tissue is,
`` `` `` `` the more limited the capacity to regenerate exists
Stimulus for regeneration

Social Order
Primary tissue culture cells grow in Petrie dish until
`` they create a confluent monolayer
`` at which time
`` `` migration and mitosis is usually down regulated

Similarly, normal cells in virtually any tissue create
`` an orderly mosaic characteristic for that tissue,
`` `` not crowding one another and
`` `` not exceeding the overall space allotted to the tissue or organ within body

There is likely a multitude of
`` `` overlapping and
`` `` redundant
`` regulatory messengers responsible for this
`` ``` “social order” within tissue

These chemical messengers are
`` `` growth factors and
`` `` cytokines
`` that
`` `` stimulate or
`` `` inhibit
`` cell proliferation of
`` `` normal and
`` `` injured tissue

Accordingly, within hours of tissue injury,
`` viable parenchymal cells at the periphery of the lesion
`` undergo
`` `` biochemical and
`` `` morphological alterations
`` that clearly indicate
`` `` “their awareness” of the
`` `` `` adjacent necrosis
`` `` `` and the need for regenerative activity

This is achieved by
`` binding of
`` `` released growth factors/cytokines to
`` `` `` cellular receptors
`` with consequential intercellular signaling
`` `` “cellular communication
Stimulus for regeneration

Social Order

Intracellular Signalling

3 Systems
Autocrine signaling:
`` Cells respond to the signaling molecules that
`` `` they themselves secrete,
`` thus establishing an autocrine loop
`` Several
`` `` polypeptide growth factors and
`` `` cytokines
`` act in this manner

Paracrine signaling:
`` One cell produces the ligand,
`` which then acts on the
`` `` adjacent target cells that
`` `` `` express the appropriate receptors
`` The responding cells are
`` `` in close proximity to
`` `` `` the ligand-producing cell
`` `` and are generally of a
`` `` `` different type
`` Paracrine stimulation is common in
`` `` connective tissue repair of healing wounds,
`` `` `` in which a factor produced by one cell type
`` `` `` `` (e.g., a macrophage)
`` `` `` has its growth effect on adjacent cells
`` `` `` `` (e.g., a fibroblast

Endocrine signaling:
`` Hormones are synthesized by
`` `` cells of endocrine organs
`` and act on target cells
`` `` distant from their site of synthesis,
`` being usually carried by the blood
``Several cytokines,
`` `` such as those associated with
`` `` `` the systemic aspects of inflammation
`` `` `` `` IL-1,
`` `` `` `` TNF
`` also act as endocrine agents
Requirements for regeneration

Regeneration will occur only

if all of the following

requirements are present: 4
Debridement

Tissue Scaffold

Available Blood Supply

Surviaval of Germinal Cells

If any of these is missing,
`` regeneration will not happen,
`` instead,
`` `` scarring and
`` `` fibrosis
`` will take place
Requirements for regeneration

Debridement is
the removal/clearing of
`` necrotic tissue by
`` `` sloughing
`` `` `` (necrotic epithelium)
`` or by
`` `` inflammatory infiltration of phagocytes
`` `` `` neutrophils and
`` `` `` especially macrophages)
Requirements for regeneration

Tissue scaffold
Parenchymal cells require a
`` scaffold
`` `` (supporting stroma)
`` upon which to grow

The normal scaffold consists of
`` the basement membrane
`` and extracellular matrix
`` `` collagen,
`` `` elastic fibers,
`` `` proteoglycans,
`` `` fibroblasts etc

Some viral and toxic injury destroy
`` `` only epithelial or
`` `` parenchymal cells
`` but not supporting stroma
`` `` allowing complete regeneration
`` `` `` if animal survives

In contrast,
`` `` ischemic necrosis or
`` `` bacterial infections
`` tend to damage
`` `` non-selectively
`` `` `` all components of affected tissue
`` tf usually repaired by
`` `` fibrosis/scarring
Requirements for regeneration

Available blood supply
Obviously,
`` adequate nutritional supply is
`` `` necessary for regeneration

Destruction of scaffolding is
`` usually associated with
`` `` destruction of blood supply as well
Requirements for regeneration

Survival of germinal cells
Survival of cells capable of motosis is
`` an absolute prerequisite
`` `` for tissue regeneration
Tissue-proliferative activity

The tissues of mammals are divided into three groups

on the basis of their proliferative activity:
labile tissues

stable tissues

permanent tissues
Tissue-proliferative activity

Labile tissues
In labile tissues
`` `` (tissue with continuously dividing cells)
`` cells proliferate
`` `` throughout life,
`` replacing those that are lost

Mature cells of most labile tissues are
`` derived from stem cells,
`` `` which have an
`` `` `` unlimited capacity to proliferate
`` `` and whose progeny may
`` `` `` undergo various streams of
`` `` `` `` differentiation

Surface epithelia:
o Stratified squamous epithelium
`` `` `` `` skin,
`` `` `` `` oral cavity,
`` `` `` `` vagina
o Mucosal epithelium
`` `` `` columnar epithelium of
`` `` `` `` gastrointestinal tract
`` `` `` `` uterus,
`` `` `` transitional epithelium of
`` `` `` `` urinary tract,
`` `` `` epithelium of
`` `` `` `` glandular ducts

Hematopoietic tissues
Tissue-proliferative activity

Stable tissues
Stable (or quiescent) tissues normally have
`` `` a low level of replication;
`` however, cells from these tissues can
`` `` undergo rapid division
`` in response to stimuli
`` and are thus capable of
`` `` reconstituting the tissue of origin

The regenerative capacity of stable cells is
`` best exemplified by the ability of
`` `` the liver to regenerate after partial hepatectomy

Parenchymal cells in
`` `` liver,
`` `` kidneys,
`` `` pancreas

Mesenchymal cells:
`` `` fibroblasts,
`` `` vascular endothelial cells,
`` `` chondrocytes, and
`` `` osteocytes
Tissue-proliferative activity

Permanent tissues
Permanent tissues
`` contain non-dividing cells that
`` `` cannot undergo mitotic division
`` `` `` in postnatal life

To this group belong
`` `` neurons and
`` `` cardiac muscle cells
`` `` `` may have limited ability

If neurons in the central nervous system are destroyed,
`` the tissue is replaced by
`` `` the proliferation of the central nervous system supportive elements
`` `` `` the glial cells
`` `` `` (forming glial scar)

If myocardial infarction occurs,
`` it will be followed by
`` `` scar formation if
`` `` `` animal survives
Morphological events of epithelial regeneration

3
Epithelial sliding
`` `` (attenuated epithelium)
`` along a
`` `` preexisting basement membrane or
`` `` a provisional matrix
`` `` `` fibrin or
`` `` `` fibronectin
`` occurs within
`` `` minutes or
`` `` hours
`` of the initial loss of epithelial continuity

Cellular proliferation
`` follows
`` `` epithelial sliding
`` to repopulate
`` `` lost epithelial cells

Maturation and normalization
`` takes sometimes
`` `` several weeks

Re-establishment of cell-matrix adhesion might
`` be initially weak and fragile
`` `` (e.g in eroded and healed cornea)
Examples of regeneration

5
Corneal epithelial erosions
`` have potential for
`` `` complete regeneration.

Atrophy of small intestinal villi
`` `` induced by porcine corona virus
`` is completely regenerated if
`` `` piglet survives

Epithelial vesicles and erosion
`` `` on bovine tongue
`` `` `` in foot and mouth disease
`` will completely regenerate if
`` `` not invaded by bacteria

Regeneration of skeletal myocytes
`` `` affected by white muscle disease i
`` s complete if
`` `` VitE/Se deficiency is corrected

Compensatory hepatic hyperplasia
`` In rodents, removal of approximately 70% of the liver
`` `` (partial hepatectomy)
`` elicits a growth response known as
`` `` liver regeneration
`` Hepatocytes in the remaining portion of the liver
`` `` rapidly proliferate
`` and the hepatic mass of the original liver is
`` `` reached in 10 to 14 days
`` Restoration of liver mass is achieved
`` `` without the regrowth of the
`` `` `` lobes that were resected at the operation
`` Thus, the end-point of liver regeneration after partial hepatectomy is
`` `` the restitution of functional mass
`` rather than form
`` More than 70 genes are activated during this comples response
`` Although much has been learned about
`` `` the steps that regulate hepatocyte replication,
`` the mechanisms of growth cessation have
`` `` not been well-established
REPAIR BY SCAR FORMATION AND FIBROSIS
With a few exceptions
`` `` that heal exclusively by regeneration,
`` majority of injuries in veterinary medicine will heal
`` `` with various degree of scarring/fibrosis

Sometimes as early as
`` `` 24-48 hours after injury,
`` if regeneration
`` `` did not occur,
`` fibroblasts and vascular endothelial cells begin
`` proliferating to form
`` `` a specialized type of tissue called
`` `` granulation tissue
REPAIR BY SCAR FORMATION AND FIBROSIS

Granulation Tissue
The term derives from its
`` `` pink,
`` `` soft,
`` `` granular
`` appearance on the surface of wounds,

histologic features are characteristic:
`` the formation of new small blood vessels
`` `` (angiogenesis)
`` and the proliferation of fibroblasts

These new vessels are
`` `` leaky,
`` allowing the passage of
`` `` proteins and
`` `` red cells
`` into the extravascular space

Thus, new granulation tissue is
`` edematous
REPAIR BY SCAR FORMATION AND FIBROSIS

Angiogenesis

What

How
The process of blood vessel formation
`` `` in adults
`` is known as
`` `` angiogenesis or
`` `` neovascularization

until recently,
`` has been thought to depend on
`` `` the branching and
`` `` extension of
`` adjacent blood vessels

Recent work has demonstrated that
`` angiogenesis can also occur by
`` `` recruitment of endothelial progenitor cells
`` `` `` from the bone marrow
REPAIR BY SCAR FORMATION AND FIBROSIS

Angiogenesis from pre-existing vessels:

6 Steps
Vasodilation
`` `` (induced by NO)
`` increased permeability
`` `` (induced by VEGF)
`` of vessels

Degradation of
`` vascular basement membrane by
`` `` proteases

Migration of
`` endothelial cells towards
`` `` angiogenic stimulus

Proliferation of
`` endothelial cells

Maturation of
`` endothelial cells and
`` `` remodeling into
`` `` `` capillary tubes

Recruitment of
`` periendothelial cells
`` `` pericytes,
`` `` smooth muscle cells
`` to support the
`` `` endothelial tubes and
`` form the mature vessel
REPAIR BY SCAR FORMATION AND FIBROSIS

Scar formation

Three processes that participate in the formation of a scar:
emigration and proliferation of
`` fibroblasts
`` `` in the site of injury

deposition of
`` extracellular matrix
`` `` (ECM)

tissue remodeling
REPAIR BY SCAR FORMATION AND FIBROSIS

Scar formation

Fibroblast migration and proliferation
Granulation tissue contains
`` numerous newly formed blood vessels

VEGF promotes
`` `` angiogenesis
`` but it is also responsible for
`` `` a marked increase in vascular permeability

The latter activity leads to
`` `` exudation and
`` `` deposition
`` of plasma proteins,
`` `` such as fibrinogen and
`` `` plasma fibronectin,
`` in the ECM
`` and provides a
`` `` provisional stroma for
`` `` `` fibroblast and
`` `` `` endothelial cell
`` `` ingrowth

Migration of fibroblasts to
`` the site of injury and
`` `` their subsequent proliferation
`` are triggered by
`` `` multiple growth factors
`` `` `` TGF-β, (trans)
`` `` `` PDGF, (platelet derived)
`` `` `` EGF, (epidermal)
`` `` `` FGF, (fibroblaast)
`` `` `` and the cytokines
`` `` `` `` IL-1 and
`` `` `` `` TNF
REPAIR BY SCAR FORMATION AND FIBROSIS

Scar formation

ECM deposition and scar formation
As repair continues,
`` the number of
`` `` proliferating endothelial cells and
`` `` fibroblasts
`` decreases

Fibroblasts progressively deposit
`` increased amounts of ECM

Fibrillar collagens form
`` a major portion of the
`` `` connective tissue in
`` `` `` repair sites
`` and are important for
`` `` the development of
`` `` `` strength in
`` `` `` `` healing wounds

Many of the same growth factors that regulate
`` `` fibroblast proliferation
`` also stimulate ECM synthesis

Ultimately,
`` the granulation tissue scaffolding is
`` `` converted into a scar composed of
`` `` `` spindle-shaped fibroblasts,
`` `` `` dense collagen,
`` `` `` fragments of elastic tissue,
`` `` `` and other ECM components

As the scar matures,
`` vascular regression continues,
`` eventually transforming the richly vascularized
`` `` granulation tissue
`` into a
`` `` pale,
`` `` avascular
`` `` contracted
`` scar
REPAIR BY SCAR FORMATION AND FIBROSIS

Scar formation

Tissue remodeling
The replacement of
`` `` granulation tissue with
`` a scar involves
`` `` transitions in the
`` `` `` composition of the ECM

Some of the growth factors that
`` stimulate synthesis of
`` `` collagen and
`` `` other connective tissue molecules
`` also modulate
`` `` the synthesis and
`` `` activation of
`` `` `` metalloproteinases,
`` enzymes that degrade these ECM components

The balance between
`` `` ECM synthesis and
`` `` degradation
`` results in
`` `` remodeling of the connective tissue framework
Cutaneous wound healing
Although most skin lesions
`` `` heal efficiently,
`` the end product may
`` `` not be functionally perfect

Epidermal appendages do not
`` `` regenerate
`` and there remains a
`` `` connective tissue scar

In very superficial wounds,
`` the epithelium is reconstituted
`` and there may be little scar formation
Cutaneous wound healing

Cutaneous wound healing is generally divided into three phases:
inflammation
`` early and
`` late

granulation tissue formation and reepithelialization

wound contraction, ECM deposition, and remodeling
Cutaneous wound healing

Skin wounds are classically described to heal by
primary or secondary intention

This distinction is based on
`` the nature of the wound
`` rather than the healing process itself
Cutaneous wound healing

Healing by first intention
(wounds with opposed edges)

Wound healing by first intention is the healing of
`` `` a clean,
`` `` uninfected surgical incision
`` approximated by surgical sutures

The incision causes
`` death of a limited number of
`` `` epithelial and
`` `` connective tissue cells
`` as well as disruption of
`` `` epithelial basement membrane continuity

The narrow incisional space
`` immediately fills with
`` `` clotted blood containing
`` `` `` fibrin and
`` `` `` blood cells

dehydration of the surface clot
`` forms the scab that covers the wound
Cutaneous wound healing

Healing by first intention

The healing process follows a series of 6 sequential steps:
Within 24 hours,
`` neutrophils are at the margins of the incision,
`` moving toward the fibrin clot

In 24 to 48 hours,
`` spurs of epithelial cells
`` `` move from the wound edges
`` `` `` with little cell proliferation
`` `` along the cut margins of the dermis
`` They fuse in the midline beneath the surface scab,
`` `` producing a continuous but thin
`` `` `` epithelial layer that
`` `` `` `` closes the wound

By day 3,
`` neutrophils have been
`` `` largely replaced by macrophages
`` Granulation tissue
`` `` progressively invades the incision space
`` Epithelial cells proliferate

By day 5,
`` the incisional space is
`` `` filled with granulation tissue
`` Collagen fibrils become
`` more abundant and
`` begin to bridge the incision
`` The epidermis recovers its
`` `` normal thickness,
`` and differentiation of surface cells yields
`` `` a mature epidermal architecture

During the second week,
`` there is continued
`` `` accumulation of collagen and
`` `` proliferation of fibroblasts
`` The
`` `` leukocytic infiltrate,
`` `` edema, and
`` `` increased vascularity
`` have largely disappeared

The long process of
`` accumulation of collagen
`` `` within the incisional scar
`` and regression of vascular channels continues

By the end of the first month,
`` the scar is made up of
`` `` a cellular connective tissue covered by
`` `` intact epidermis
``The dermal appendages that have been destroyed in the line of the incision are
`` `` permanently lost
`` Tensile strength of the wound
`` `` increases thereafter,
`` `` `` but it may take
`` `` `` `` months
`` `` for the wounded area to obtain
`` `` ``its maximal strength
Cutaneous wound healing

Healing by second intention
(wounds with separated edges)

Healing by second intention is characterized by
`` more extensive loss of
`` `` cells and
`` `` tissue,
`` as in surface wounds that create large defects
`` the reparative process is
`` `` more complicated.

Regeneration of parenchymal cells
`` `` cannot completely restore the original architecture,
`` and hence
`` `` abundant granulation tissue grows
`` `` `` in from the margin
`` to complete the repair
Cutaneous wound healing

Differences between healing by first and second intention: 3
Large tissue defects
`` generate a larger fibrin clot
`` `` that fills the defect
`` and more
`` `` necrotic debris and
`` `` exudate
`` that must be removed
`` Consequently the inflammatory reaction is
`` `` more intense

Much larger amounts of granulation tissue are formed

Substantial scar formation
`` and thinning of the epidermis
Wound strength
At the end of the first week,
`` wound strength is
`` `` approximately 10% that of unwounded skin,
`` but strength increases rapidly over
`` `` the next 4 weeks

Approximately thee months after the original incision,
`` the wound reaches a
`` `` plateau at about
`` `` `` 70% to 80%
`` of the tensile strength of unwounded skin

The tensile strength results from
`` the excess of
`` `` collagen synthesis
`` over
`` `` collagen degradation
`` and from
`` `` structural modifications of collagen fibers
Complications in wound healing

5
Deficient Scar formation

Excessive formation of Repair components

Fibrinous
`` pleuritis
`` peritonitis
`` pericarditis

Circumfrential Chrinic Ulceration

Hepatic Cirrhosis
Complications in wound healing

Deficient scar formation
Deficient scar formation
`` Inadequate formation of
`` `` granulation tissue
`` `` or assembly of a scar
`` can lead to two types of complications:
`` `` wound dehiscence
`` `` ulceration
Complications in wound healing

Excessive formation of the repair components
Excessive formation of the repair components
`` Formation of excessive amounts of
`` `` granulation tissue,
`` `` `` which protrudes above the level of the surrounding skin and
`` `` blocks re-epithelialization
`` This has been called
`` `` exuberant granulation
`` `` `` (or proud flesh)
`` in horses.
Complications in wound healing

Fibrinous pleuritis, peritonitis, and pericarditis
Fibrinous pleuritis, peritonitis, and pericarditis
`` often heal through scar formation,
`` `` creating adhesions between the
`` `` `` visceral and parietal layers of these tissues
`` The development of a dense, fibrous scar in the pericardium
`` `` can lead to a serious condition called
`` `` `` constrictive pericarditis
Complications in wound healing

Circumferential chronic ulceration
Circumferential chronic ulceration
`` with subsequent fibrosis of a tubular organ
`` can cause
`` `` constriction.
Complications in Wound Healing

Hepatic cirrhosis –
Hepatic cirrhosis –
`` often fatal by virtue of
`` `` progressive downward spiral of injury:
`` `` `` fibrosis,
`` `` `` ischemia,
`` `` `` necrosis,
`` `` `` hepatocellular proliferation,
`` more fibrosis,
`` more ischemia,
`` more necrosis and
`` more hepatocellular proliferation.
Wound Healing

Growth factors

5
There is a large number of known growth factors that
`` stimulate cell proliferation
`` and are involved in would healing.

Epidermal Growth Factor (EGF)
`` is mitogenic for a variety of
`` `` epithelial cells,
`` `` hepatocytes, and
`` `` fibroblasts
`` It is widely distributed in tissue secretions and fluids, such as
`` `` sweat,
`` `` saliva,
`` `` urine, and
`` `` intestinal contents

Vascular Endothelial Growth Factor (VEGF)
`` is a potent inducer of blood vessel formation in early development
`` `` (vasculogenesis)
`` and has a central role in
`` `` the growth of new blood vessels
`` `` (angiogenesis)
`` in adults
`` It promotes angiogenesis in
`` `` tumors,
`` ` chronic inflammation,
`` `` and healing of wounds

Platelet-Derived Growth Factor (PDGF)
`` is stored in platelet α granules
`` and is released on platelet activation
`` It can also be produced by
`` `` macrophages,
`` `` endothelial cells
`` `` etc
`` PDGF causes
`` `` migration and
`` `` proliferation
`` of
`` `` fibroblasts,
`` `` smooth muscle cells, and
`` `` monocytes

Fibroblast Growth Factors (FGF) (>10 members)
`` have a large number of functions,
`` `` in addition to those involved in wound healing
`` migration of
`` `` macrophage,
`` `` fibroblast,
`` `` endothelium and
`` `` epidermis

Transforming Growth Factor β (TGF-β)
`` has multiple and often opposing effects
`` depending on
`` `` the tissue and
`` `` the type of injury:
`` growth inhibitor for most
`` `` epithelia and
`` `` leukocytes;
`` generally stimulates
`` `` proliferation and
`` `` chemotaxis
`` of fibroblasts
``and production of
`` `` collagen,
`` `` fibronectin, and
`` `` proteoglycans
`` TGF-β is involved in the development of
`` fibrosis in a variety of
`` `` chronic inflammatory conditions
`` `` `` particularly in the
`` `` `` `` lungs,
`` `` `` `` kidney, and
`` `` ` `` liver
`` TGF-β has a strong anti-inflammatory effect
Wound Healing

Growth factors

Transforming Growth Factor β (TGF-β)
has multiple and often opposing effects
`` depending on
`` `` the tissue and
`` `` the type of injury:

growth inhibitor for most
`` `` epithelia and
`` `` leukocytes;

generally stimulates
`` `` proliferation and
`` `` chemotaxis
`` of fibroblasts
``and production of
`` `` collagen,
`` `` fibronectin, and
`` `` proteoglycans

TGF-β is involved in the development of
`` fibrosis in a variety of
`` `` chronic inflammatory conditions
`` `` `` particularly in the
`` `` `` `` lungs,
`` `` `` `` kidney, and
`` `` ` `` liver

TGF-β has a strong anti-inflammatory effect
GENERAL FEATURES OF THE IMMUNE SYSTEM
Function of the immune system is to protect animals from pathogens.

The mechanisms that are responsible for this protection fall into two broad categories:

innate immunity (also called constitutive or native immunity)

adaptive immunity (also called acquired or specific immunity
Innate immunity
Innate immunity refers to
`` defense mechanisms that are present even before infection
`` `` (without requirements of previous exposure to pathogen/antigen)

Have evolved to specifically
`` recognize microbes
`` and protect multicellular organisms against infections
The major components of innate immunity are:
1. Barriers

2. Acute phase response

3. Humoral innate immunity

4. Cellular innate immunity
Innate Immunity

Barriers 3
Physical barriers
`` Static barriers:
`` `` epithelial surfaces prevent pathogen invasion
`` Kinetic barriers:
`` `` `` mucociliary clearance of respiratory tract
`` `` `` peristalsis in gastrointestinal tract
`` removes pathogens form the host surfaces

Biological barriers:
`` normal microflora of
`` `` gastrointestinal,
`` `` upper-respiratory and
`` `` dermal surfaces `` competitively inhibits
`` `` colonization and
`` `` invasion
`` by pathogens

Chemical:
`` gastric hydrochloric acid
`` `` kills many ingested pathogens
Innate Immunity

Acute phase response 3
Acute phase proteins

Systemic reactions:
`` fever,
`` chills
`` `` (search for warmth),
`` anorexia
`` somnolence

Systemic hypoferremia
``to withhold iron from invading pathogens
Innate Immunity

Humoral innate immunity 4
Microbicidal components:
`` MAC of complement
`` Defensins and lysozyme
`` `` secreted on
`` `` `` mucosal and
`` `` `` dermal surfaces

Microbiostatic components
`` Metal binding proteins
`` `` transferrin,
`` `` lactoferrin

Opsonins
`` Lectins:
`` `` mannose binding lectin,
`` `` C-reactive protein,
`` `` surfactant(-like) proteins

Acute phase proteins
Innate Immunity

Cellular innate immunity
Phagocytes
`` macrophages and
`` neutrophils

Natural killer (NK) cells
Adaptive immunity

Adaptive immunity consists of
mechanisms that are stimulated by (adapted to)
`` previous exposure to microbes
`` and are capable of also
`` `` recognizing non-microbial substances,
`` `` called antigens.

Innate immunity is the first line of defense, because it
`` is always ready to
`` `` prevent and
`` `` eradicate infections

Adaptive immunity develops later after
`` exposure to microbes and
`` is even more powerful in combating infections
Adaptive immunity

There are two main types of adaptive immunity:
cellular immunity
`` `` (mediated by T- lymphocytes),
`` which is responsible for defense against
`` `` intracellular microbes,

humoral immunity
`` `` (mediated by B lymphocytes and their secreted antibodies),
`` which protects against
`` `` extracellular microbes and their toxins.
Adaptive immunity

Although vital to survival, the immune system is similar to
the proverbial two-edged sword

On the one hand,
`` immunodeficiency states render animal to be an
`` `` easy prey to infections

on the other hand,
`` a hyperactive immune system may cause
`` `` fatal disease
Adaptive immunity

failure to distinguish self from non-self may result in
immune reactions against animal’s own tissues
`` autoimmunity
Immunodeficiency disorders can be divided into
primary immunodeficiency
`` (inherited)

secondary immunodeficiency
`` (acquired)
Primary immunodeficiencies

Primary immunodeficiencies are
rare in animals
Primary immunodeficiencies

Chediak-Higashi syndrome
Hereford cattle, Persian cats etc

Defective killing of
`` phagocytosed microorganisms
`` due to abnormal lysosomes

Abnormal pigmentation of melanocytes
Primary immunodeficiencies

Leukocyte adhesion deficiency
Irish setters and Holsteins

Persistent neutrophilia

Defect in ß2 integrin,
`` therefore circulating neutrophils
`` `` cannot bind firmly to endothelium
`` `` `` and exit blood vessels towards infection site
Primary immunodeficiencies

Severe combined immunodeficiency (SCID)
Arabian foals, dogs and mice

Defects in both
`` humoral and
`` cell-mediated immune responses

Affected Arabian foals are
`` clinically normal from
`` `` birth to 1-3 months
`` when they are protected by
`` `` passively transferred colostral maternal immunoglobulins
`` The loss of passive immunity
`` combined with the humoral and cellular immunodeficiency result in
`` `` fatal respiratory and
`` `` gastrointestinal infections
`` `` `` adenovirus,
`` `` `` Pneumocystis carinii,
`` `` `` common bacteria

Gross lesion:
`` small or absent thymus
`` and lesions associated with infections
`` `` pneumonia
Secondary immunodeficiencies

Acquired (secondary) immunodeficiencies are
much more common in animals than primary immunodeficiencies
Secondary immunodeficiencies

Animal AIDS
Simian immunodeficiency virus (SIV) in Old World monkeys
`` (e.g. rhesus – Macaca mulatta)

Feline immunodeficiency virus (FIV)
`` During the prolonged asymptomatic period,
`` `` progressive loss of T-lymphocytes results in
`` `` `` immunodeficiency with
`` `` `` `` consequential chronic and recurrent opportunistic infections
`` `` `` `` `` which are eventually fatal
`` (Gingivitis is often the first sign of FIV infection
`` Biting is the principal mode of
`` `` FIV transmission,
`` `` `` accordingly, highest incidence is in
`` `` `` `` outdoor male cats
Secondary immunodeficiencies

Lymphotropic viruses
Bovine viral diarrhea virus is
`` `` epitheliotropic and
`` `` lymphotropic
`` Accordingly it causes
`` `` erosions in the
`` `` upper alimentary tract
`` `` `` mouth,
`` `` `` esophagus and
`` `` `` rumen
`` `` and in the
`` `` `` interdigital areas
`` `` as well as marked generalized lymphoid depletion
`` `` `` necrosis of Peyers patches

Canine parvovirus and feline panleukopenia (parvovirus) virus
`` affect proliferating cells;
`` accordingly, it destroys
`` `` predominantly cryptal epithelial cells
`` `` `` in small intestines causing
`` `` `` `` enteritis and
`` `` `` mild peritonitis
`` `` and bone marrow cells
`` `` `` causing panleukopenia and
`` `` `` Peyers patches necrosis
Secondary immunodeficiencies

Failure of passive transfer of immunoglobulins
This is the most common immunodeficiency disorder in domestic animals

Mammalian neonates are born with
`` naïve acquired (specific) immune systems,
`` `` such that they rely heavily on
`` `` `` immune protection provided by their
`` `` `` `` mother’s colostrum and milk

This colostral immune protection is particularly important for
`` neonates of species with
`` `` epitheliochorial placentation,
`` `` `` wherein the placenta is impermeable to
`` `` `` `` large molecules such as immunoglobulins

Accordingly, these neonates are born
`` hypogammaglobulinemic and,
`` `` therefore, must rely on colostral immunoglobulins,
`` `` `` which are absorbed across their
`` `` `` `` gastrointestinal tracts during the first
`` `` 24-48 hours of life

Failure to do so results in
`` increased susceptibility to infections
`` and majority of these neonates will
`` die due to
`` `` septicemia often accompanied by
`` `` `` fibrinous/fibrinopurulent
`` `` `` `` meningitis,
`` `` `` `` polyarthritis and
`` `` `` `` polyserositis
Secondary immunodeficiencies

Steroid induced immunodeficiency/immunosuppression
immunosuppression
`` and increased susceptibility to
`` `` infectious diseases
`` can result from

Chronic stress,

adrenal cortical tumor

prolonged steroid therapy
Secondary immunodeficiencies

Other causes
- Malnutrition

- Chemotherapy

- Radiation therapy

- Age
Four basic immune reactions -
types I, II, III, and IV -

mediate the tissue damage in
`` hypersensitivity and
`` autoimmune diseases
Hypersensitivity is
an exaggerated immunological reaction to a
`` normally harmless antigenic stimulus resulting in
`` injury to the host

Prior sensitization to a specific antigen is
`` required
Hypersensitivity disorders tend to be
mediated by type
`` I and
`` IV
reactions
Autoimmune diseases develop
when
`` `` antibodies or
`` `` T cells
`` are reactive against
`` `` self-antigens
Autoimmune diseases tend to be
mediated by type
`` II or
`` III
reactions

although more than one mechanism may be involved
Autoimmune diseases

Type I reactions
(immediate hypersensitivity)

Mediated by active substances
`` `` (e.g. histamine)
`` released or formed de novo by
`` `` mast cells and
`` `` basophils
`` following reaction between
`` `` antigen and
`` `` specific antibody
`` `` `` (usually IgE)
`` bound to receptors on
`` `` the membrane of the
`` `` `` mast cells or
`` ``` `` basophils

Can be systemic and/or local

Inherited predisposition exists

Examples:
`` atopic dermatitis,
`` insect bite hypersensitivity,
`` food allergy,
`` drug eruption,
`` anaphylaxis
Autoimmune diseases

Type II reactions
(cytotoxic hypersensitivity)

Cytotoxic reactions involving interaction of
`` `` IgG or
`` `` IgM
`` with antigens bound on
`` `` cellular membranes
`` complement fixation frequently occurs,
`` `` leading to cellular damage

Cell damage is mediated by:
`` Complement
`` Antibody-dependent cell-mediated cytotoxicity
`` Antibody-dependent cell dysfunction

Examples:
`` pemphigus,
`` iso-immune thrombocytopenia,
`` immune mediated hemolytic anemia,
`` myasthenia gravis
Autoimmune diseases

Type III reactions
[immune-complex (Arthus) hypersensitivity]

Immune complexes
`` `` IgG or IgM + antigen
`` deposit in tissues
`` `` and fix complement generating
`` `` `` cytokines and other factors that
`` `` `` `` attract neutrophils

Examples:
`` immune mediated glomerulonephritis,
`` equine purpura hemorrhagica (S. equi),
`` systemic lupus erythematosus,
`` feline infectious peritonitis
Autoimmune diseases

Type IV reactions
(delayed hypersensitivity)

Mediated by
`` sensitized T cells that,
`` `` after contacting a specific antigen,
`` `` `` release cytokines attracting
`` `` `` `` macrophages and/or
`` `` `` `` recruit other lymphocytes that are cytotoxic

Examples:
`` some drug eruptions,
`` granulomatous diseases
`` `` tuberculosis
Atopy
(atopic dermatitis, allergic inhalant dermatitis)

Type I hypersensitivity reaction

Skin is the major target organ in
`` dogs,
`` cats, and
`` horses

Route of allergen exposure is
`` suspected to be predominantly respiratory
`` `` (at least in dogs)

There is an inherited predisposition to
`` develop immediate hypersensitivity reaction to
`` `` a variety of antigens by
`` `` `` excessive production of IgE
`` which, when coupled to a
`` `` specific antigen, trigger
`` `` `` degranulation of
`` `` `` `` dermal mast cells and
`` `` `` `` circulating basophils

Lesions:
`` erythema,
`` urticaria,
`` self-inflicted trauma
`` `` `` licking,
`` `` `` rubbing
`` `` due to pruritus
Erythema -
redness due to capillary dilation
Urticaria -
eruption of itching wheals
`` acute dermal edema and
`` erythema
Food hypersensitivity dermatitis
Type
`` `` I and/or
`` `` type IV
`` reaction to food antigens

Non-seasonal pruritic disease in young dogs

Lesions:
`` erythema,
`` urticaria,
`` self-inflicted trauma
`` `` `` licking,
`` `` `` rubbing
``` `` due to pruritus
Pemphigus
Dermal disease caused by
`` type II reaction.

Pathogenesis:
`` Development of antidesmosomal auto-antibodies
`` `` which bind to desmosomal proteins
`` `` (interepithelial attachment proteins)
`` and, subsequently,
`` `` disruption of cell-cell adhesion,
`` resulting in formation of intraepithelial pustules

Lesions:
`` intraepithelial pustules
`` `` muzzle,
`` `` periocular,
`` `` pinnae,
`` `` foot pads,
`` `` around nails
`` or erosions following pustular ruptures
Acquired Myasthenia Gravis
-
Systemic muscular disease caused by
`` type II reaction
`` `` mediated by antibody-dependent dysfunction

Auto-antibodies are developed against
`` acetylcholine receptors
`` `` which are then masked by attached antibodies;
`` therefore, receptors cannot
`` `` interact with acetylcholine

Clinical signs:
`` muscle weakness and fatigue
`` `` exacerbated by exercise
`` and resolves with rest

It is most commonly seen in
`` adult dogs that might have megaesophagus
`` `` +/- aspiration pneumonia
Iso-immune thrombocytopenia in piglets
Sows are sensitized to
`` platelet antigens of
`` `` fetal piglets
`` and develop anti-platelet antibodies
`` `` that are secreted into colostrum

Ingested colostral antibodies are
`` absorbed by piglets

the antibodies bind to platelets
`` and platelets are subsequently destroyed

This results in
`` thrombocytopenia
`` and widespread hemorrhages
Neonatal isoerythrolysis in foals
mare is sensitized to
`` erythrocytic antigens of a foal
`` and develops anti-erythrocyte antibodies that
`` `` are secreted into colostrum

Ingested colostral antibodies are
`` absorbed by a foal;

the antibodies bind to
`` erythrocytes, which are
`` `` subsequently destroyed by
`` `` `` complement
`` `` `` `` (intravascular hemolysis)

This may result in
`` fatal anemia,
`` icterus,
`` hemoglobinemia and
`` hemoglobinuria
Idiopathic immune-mediated haemolytic anemia
most common in dogs.

Auto-antibodies are developed against
`` erythrocytic antigens

Erythrocytes coated by antibodies
`` `` (IgG)
`` are phagocytosed by macrophages
`` `` predominantly in spleen
`` `` `` (extravascular hemolysis)
`` and sometimes lysed
`` `` (hemolysis)
`` by complement
`` `` (intravascular hemolysis)
`` with IgM

The most common lesions:
`` regenerative anemia,
`` icterus,
`` enlarged spleen
`` `` due to
`` `` `` activation ofmacrophages and
`` `` `` extramedullary hematopoiesis
`` bone marrow hyperplasia
`` `` diffusely red
Equine purpura haemorrhagica
After Streptococcus equi infection
`` `` (strngles)
`` small percentage of horses have
`` `` high level of antigen
`` `` `` (protein M)
`` `` antibody
`` `` `` IgA and
`` `` `` IgM
`` complexes in circulation

which are deposited in vessels
`` tf
`` `` consequential vasculitis,
`` `` generalized edema and
`` `` purpura
Feline infectious peritonitis
It is a
`` `` progressive
`` `` fatal
`` immune-mediate disease of cats
`` caused by a coronavirus

FIP virus is spread systemically by
`` infected macrophages

Immune complexes
`` `` (virus+Ab or viral antigen+Ab)
`` are deposited on venular walls and cause
`` `` type III immune reaction

Based on experimental infections it seems that
`` the ultimate outcome of FIP viral infection depends
`` `` on cell mediated immunity
`` `` `` (CMI)

If CMI is strong and rapid
`` virus will be contained
`` `` (latent carrier)
`` and subsequently eradicated

If CMI is weak,
`` effusive form of FIP will occur
`` with marked fibrinous exudation in
`` `` serosal cavities

If CMI is moderately strong,
`` dry form with
`` `` granulomatous/pyogranulomatous infiltrate
`` will occur in many organs
`` `` kidney,
`` `` liver,
`` `` lung,
`` `` eyes,
`` `` meninges,
`` `` etc
AMYLOIDOSIS

Amyloid is a
pathologic proteinaceous substance,
`` deposited between cells in
`` `` various tissues and organs of the body
`` in a wide variety of
`` `` clinical settings
AMYLOIDOSIS

Clinical diagnosis of amyloidosis

ultimately depends on
morphologic identification of
`` amyloid in biopsy specimens by
`` `` light microscopy

Amyloid is
`` `` amorphous,
`` `` eosinophilic,
`` `` hyaline,
`` `` extracellular
`` `` substance that has
`` characteristic histochemical properties
`` `` Congo red stain,
`` `` `` which under ordinary light imparts a
`` `` `` `` pink or red color to tissue deposits,
`` `` `` but far more dramatic and specific is
`` `` `` `` the green birefringence of the stained amyloid
`` `` `` `` `` when observed by polarizing microscopy
AMYLOIDOSIS

Despite the fact that all deposits have

a uniform appearance
(ß-pleated sheet fibrils)
`` and tinctorial characteristics,

amyloid is not a chemically distinct entity
Amyloidosis

AA

AL

IAPP
Serum amyloid A
`` Chronic inflammation

Ig light chain
`` Plasmacytoma

Islet amyloid polypeptide
`` Pancreatic islets
AA amyloidosis is
most common systemic form in animals

It originates from
`` serum amyloid A
`` `` that is an acute phase protein in many species

Concentration of SAA is increased during
`` inflammatory diseases,
`` even though its function is
`` `` not known.
AL amyloidosisis
rarely seen in animals
`` it is largely a disease of humans

In dogs
`` AL amyloidosis is associated with
`` localized plasmacytomas
IAPP amyloidosis is
relatively common in
`` old cats and
`` non-human primates

Pancreatic islet amyloidosis is associated with
`` diabetes mellitus in
`` cats

Islet amyloid polypeptide (IAPP) is
`` a normal component co-secreted with
`` `` insulin by
`` `` `` ß-cells

However, if IAPPs change conformation
`` and are deposited in
`` `` islets,
`` `` `` amyloidosis will occur
Renal amyloidosis
Animals with progressive renal amyloidosis
`` die with
`` `` renal failure and
`` `` uremia

Kidneys of these animals are
`` enlarged and
`` pale yellow-brown

Amyloid may be accumulated in
`` `` glomeruli,
`` `` below basement membrane of renal tubules and
`` `` in small arterioles

Glomerular amyloidosis interferes with
`` normal filtration
`` and results in
`` `` proteinuria

Ultimately, amyloid interferes with
`` `` blood supply to the
`` `` entire nephron and
`` `` `` renal tubular atrophy with
`` `` `` `` uremia
`` `` `` occurs