VTPA 342 Repair and Immunopathology
Terms
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- 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 communicationï€ -
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
שּׂ -
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