Download Diseases of Immunity - CL Davis Foundation

Diseases of Immunity
2011 CL Davis
General Pathology
Paul W. Snyder, DVM, PhD
Purdue University
Hypersensitivity reactions
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Altered reactivity to an antigen that results in
pathologic reactions upon the exposure of a
sensitized host to that antigen.
Four different types based on the mechanism
(effector molecules) by which the immune reactions
initiate the tissue injury:
• Humoral immunity
• Cell mediated immunity
“Over reactive immune response”
Immune reaction elicits an inflammatory response
that is more harmful than the pathogen or antigen.
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Classification of hypersensitivity
Hypersensitivity
Reactants
Antibodies
Cells
Reaction type
I
II
III
IV
Major mediator
IgE
IgG
IgG
T cells
Allergens
Insoluble
Soluble
Soluble & Insoluble
Antigens
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Type I hypersensitivity reactions
• Immediate hypersensitivity, anaphylactic reaction or allergy.
• Immunologic reaction that manifests itself by tissue reactions
within minutes after exposure.
• Cells involved:
– Mast cell
– Plasma cell
– Eosinophil
• Mediators involved:
– Histamine
– AA products
– ECF
– Proteases
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Type I hypersensitivity: Components
• Antibody IgE:
– Reagenic antibody
– Extra heavy chain domain on constant portion
– Low serum levels in the dog:
• IgG 1000-2000 mg/dL
• IgM 100-200 mg/dL
• IgA 30-240 mg/dL
• IgE 2-40 mg/dL
– CH2 domain binds to mast cells via Fc receptor
– Longer half-life when bound (weeks vs. days)
– Genetically determined ability to form IgE
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Type I Hypersensitivity: Components
• Mast cell:
– Metachromatic granules
– Connective tissue vs. mucosal mast cells
– Localized release of mediators
• Mechanism of mast cell degranulation:
– Allergen cross-links receptor bound antibody
– Changes in cyclic nucleotide levels
• cAMP
• cGMP
– Influx of calcium
– Methylation of membrane phospholipids
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Type I hypersensitivity: Pathogenesis
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Sensitization of the host
Production of antibody (IgE)
Antibody fixes to the surface of mast cells
Host is now sensitized
Second exposure to the antigen results in cross linking of IgE
on the mast cell surface
• Activation of the mast cell
– pre-formed mediators
– newly synthesized mediators
• Inflammatory reaction
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Type I hypersensitivity: Consequences
• Conditions range from life-threatening (systemic anaphylaxis
and asthma) to annoying localized reactions (dermatitis and
rhinitis).
• Mediators result in:
– Increased vascular permeability
– Smooth muscle contraction
– Influx of inflammatory cells
– Tissue damage
• Reaction may be systemic or localized.
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IL-4
IL-5
IL-6
TNF
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Type I hypersensitivity: Components
• Eosinophils:
– Allergic and parasitic reactions
– ECF and LTB4 are chemotactic for eosinophils
– Major basic protein and lysosomal enzymes
– Diamine oxidase and arylsulfatase (anti AA products)
– Some anti-inflammatory effects but still largely proinflammatory overall.
• Allergens:
– Proteins, Plant pollens, Drugs, Foods, Insect venoms,
Molds, Animal hair/dander
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Regulation of the Type 1 Response
• TH1- decreases the response
– IFN 
• TH2- increases the response
– IL-3, mast cell production
– IL-4, class switching to IgE
– IL-5, eosinophil maturation and activation
– IL-10, mast cell production
• Soluble antigens
– Fail to elicit a co-stimulatory signal, anergy
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Type I hypersensitivity: Specific disease
syndromes
• Target organ depends on the route of administration of the
antigen.
• Atopic dermatitis:
– A familial tendency to develop a localized type I hypersensitivity
reaction
– Genetic predisposition to develop IgE antibodies and clinical allergy to
environmental allergens
– Involves the skin in dogs
– Breeds predisposed (Terriers and Dalmations)
– Clinically present with erythema, edema and papules
– Secondary changes include hyperpigmentation and alopecia
– Serum concentrations of IgE are variable
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Type I Hypersensitivity:
Specific diseases
• Acute systemic anaphylaxis:
– Systemic type I hypersensitivity
– Occurs with rapid administration of an antigen to a
sensitized host
• Food allergy
– Skin or GI signs
• Allergies to vaccines, drugs, parasites...
• Laminitis
• Milk allergy
– Cattle allergic to casein
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Type II Hypersensitivity
Cytotoxic reactions
• Defined as the binding of an antibody to an antigen on the
surface of a cell such that the cell is destroyed
• Pathogenesis
– Antibody activates the complement system (MAC)
– Cell is opsonized and removed or destroyed by the RE
system in the liver or spleen
– Cell surface antigen elicits an antibody response >
antibodies bind to the cell > the cell is either lysed or
complement components attract phagocytic cells >
damage to tissues from the release of proteolytic enzymes.
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Cytotoxic reactions: Specific disease
syndromes
• Anti-receptor antibodies
• Antibody binds to a cell receptor and either activates or
blocks the activation of the cell
– Myasthenia gravis, anti-Ach receptor antibodies block
– Graves disease –hyperthyroidism from anti-TSH receptor
antibodies activate
– Other endocrine organs
– Most frequently involves IgG and IgM
• Inflammatory reaction results in tissue damage
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Stimulating antibodies
Blocking antibodies
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Cytotoxic reactions: Specific disease
syndromes
• Hematologic diseases
• Cytotoxic reactions are most commonly seen in hematologic
diseases due to cell surface antigens present on RBC’s,
platelets, etc.
• Immune mediated hemolytic anemia
• Autoimmune hemolytic anemia
• Blood groups-alloantibody induced
– Complex system of antigens on the surface determine the
blood group
– Genetically controlled
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Cytotoxic reactions: Transfusion
reactions
• Incompatible blood transfusions where the recipient has
natural antibodies or becomes sensitized to antigens on the
surface of allogeneic RBC’s
• First transfusion sensitizes the recipient and second results in
an anamnestic response
• Cross matching
– Major- mixing of donor RBC’s with recipient serum
– Minor – mixing of donors serum with recipient RBC’s
– Antigen-antibody reactions can be temperature sensitive
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Cytotoxic reactions: Hemolytic Disease
of the Newborn
• Neonatal isoerythrolysis
• Females sensitized to the blood group antigens of their young
will produce antibodies which can be passed to the newborn
in the colostrum and are absorbed
• Heterophile antigens common to a number of organisms
– M antigen
– Forsman antigen
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Passive transfer of antibody
Species
Placenta type
Primates
hemochorial
IgG
transfer
100%
Dogs, cats
endotheliochorial
5-10%
Pigs, Horses
epitheliochorial
0%
Ruminants
syndesmochorial
0%
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Neonatal isoerythrolysis
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Anti-erythrocyte antibodies
Aa and Qa blood types
Testing foals RBC with colostrum
• Rouleaux formation complicates
Hemolysis test
• Foals RBC, exogenous IgG, NRS (C’)
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Hemolytic disease of the newborn:
Foal
• Four conditions:
– Mare inherits a unique blood group antigen
– Mare must be sensitized
– Mare must be boosted late gestation
– Foal must ingest and absorb antibodies
• Direct antiglobulin (Coombs) test
– Foals RBC + mares serum
• Treatment?
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Diseases with a Type II Pathogenesis
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Pemphigus diseases
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Intercellular junctions
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Bullous pemphigoid
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Epidermal cadherin, desmoglein 1
Collagen type XVII within hemidesmosomes
Pernicious anemia
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Intrinsic factor of gastric parietal cells
Decreased B12 absorption
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Cytotoxic reactions: Drug reactions
• Many drugs non-specifically bind to the surface of RBC’s and if
the patient is producing antibodies against the drug these
antibodies will also bind to the RBC bound drug and activate
complement
• Some drugs are capable of altering the RBC surface antigens
and the immune system recognizes them as foreign
• Many drugs are haptens
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Cytotoxic Reactions: Infectious agents
• Absorption of bacterial, viral, protozoal, etc. antigens to the
surface of RBC may also result in new antigenic determinants
and the initiation of an antibody response
• In most instances the actual antigen is unknown
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Type II Hypersensitivity: Diagnosis
• Immune mediated hemolytic anemias
• Indirect Coombs test: patients serum and test RBC from the
same species
• Direct Coombs test: patients RBC and anti-IgG, anti-IgM and
anti-C3 (Coombs reagent)
+ Coombs
Reagent
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Type III Hypersensitivity:
Immune Complex-mediated
• “Innocent bystander”
• Immune complexes are formed and either stick onto a cell or
are deposited in that tissue.
• Pathogenesis: immune complex formation > complexes
become lodged or deposited in tissues > complement
activation > anaphylatoxins, chemotactic factors > neutrophil
infiltration and activation > release of enzymes > tissue
damage
• Cell or tissue injury is similar to that in a type II reaction even
though the pathogenesis is different.
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Type III Hypersensitivity
• Most often involves IgG and IgM
• Antibody > antigen. The complexes are large and insoluble,
and are normally removed from circulation by the MPS.
• Antigen > antibody. The complexes remain small and soluble,
and become trapped beneath endothelial cells along
basement membranes.
• In extreme antigen excess the complexes are too small to
become lodged and the immunoglobulin is incapable of
complement activation.
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Type III Hypersensitivity
• Pathology:
– Vascular lesions with a predominance of neutrophils
– Site and amount of complex deposition determines the
severity and significance
– Most often deposited in filtering structures, therefore their
accumulation is and anatomic and physiologic process with
no immunologic basis
• Blood vessels
• Glomeruli
• Skin
• Joints
• RBC and platelets Snyder 2010
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Type III Hypersensitivity:
Local reactions
• Arthus reaction: parenteral administration of an antigen to an
animal that has circulating antibody specific for the antigen.
• Blue-eye: anterior uveitis leading to corneal edema and
opacity. Canine type 1 adenovirus infections.
• Hypersensitivity pneumonitis, alveolitis and vasculitis in
animals sensitized to inhaled antigens. Micropolyspora faeni.
• Staphylococcal hypersensitivity: Staphylococcus aureus.
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Type III Hypersensitivity :
Generalized reactions
• Serum sickness: heterologous antisera to provide antibody
against a particular antigen.
– Fever
– Vasculitis
– Arthritis
– Glomerulonephritis
• Clinical manifestations are dependent on:
– Quantity of complexes
– Size of complexes
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Type III Hypersensitivity:
Generalized reactions
• Virally-induced: repeated or persistent presence of moderate
amounts of antigen accompanied by low level antibody
production.
• Bacterially-induced
• Drug Reactions
– Allergies to penicillin and sulfonamides
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Infectious Diseases
Erysipelothrix rhusiopathae
Mycobacterium johnei
Streptococcus equi
Staphlococcus aureus
Borrelia burgdorferi
Ehrlichiosis
Canine adenovirus 1
Canine adenovirus 2
Feline leukemia
Feline infectious peritonitis
Aleutian disease
Hog cholera
African swine fever
Bovine virus diarrhea
Equine viral arteritis
Equine infectious anemia
Visceral leishmaniasis
Dirofilaria immitis
Arthritis
Enteritis
Purpura
Dermatitis
Glomerulonephritis
Glomerulonephritis
Uveitis, glomerulonephritis
Glomerulonephritis
Glomerulonephritis
Peritonitis, glomerulonephritis
Glomerulonephritis, arteritis, anemia
Glomerulonephritis
Glomerulonephritis
Glomerulonephritis
Arteritis
Anemia, glomerulonephritis
Glomerulonephritis
Glomerulonephritis
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Type III Hypersensitivity
Autoimmune Diseases
• Systemic lupus erythematosus
– autoantibodies, anti-DNA
• Rheumatoid arthritis
– IgM anti-IgG (rheumatoid factor)
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Type III Hypersensitivity
Diagnosis
• Indirect immunofluorescence with anti-IgG, anti-IgM
and anti -C3.
Immune complex
Blood vessel
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Type IV Hypersensitivity:
Cell-mediated or delayed
hypersensitivity
• Results from sensitization of T lymphocytes.
• Resulting immune response is mediated by either
direct cytotoxicity or by the release of cytokines
which activate macrophages.
• Immunologically specific.
• Mononuclear inflammatory cells.
• Transferable with lymphoid cells and not serum.
• Dependent on T lymphocytes.
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Type IV Hypersensitivity
• Pathogenesis: binding of antigen to sensitized T lymphocytes
> cytokine synthesis (attract, activate, immobilize) >
lymphocyte proliferation > generation of cytotoxic T
lymphocytes > infiltration of macrophages.
• 24-48 hours to develop.
• TH1 cells.
• Cytokines:
– IL-2
– IFN 
– macrophage migration-inhibition factor (MIF)
– TNF 
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Type IV Hypersensitivity
Classical example
• Tuberculin reaction.
• Tuberculin refers to extracts of M. tuberculosis, M. bovis or M.
avium.
• Intradermally administered.
• Purified protein derivative (PPD).
• Positive reaction.
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Type IV Hypersensitivity
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Allergic contact dermatitis
• Langerhans cells process antigen
and present to naïve T cells in lymph
nodes (sensitization).
• Horses, dogs and rarely cats
• Numerous causes: plants, plastics,
insecticides, flea collars, etc.
• Haptens
Demodecosis - Demodex canis
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Type IV Hypersensitivity
Lesions
• Delayed type hypersensitivity vs cell mediataed immunity
– Beneficial = immunity
– Harmful = hypersensitivity
• Granulomatous inflammation
– Epitheliod macrophages, multinucleated giant cells
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Pathogens and Contact Antigens Associated With
a Type IV Pathogenesis
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Bacteria
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Viruses
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Dimorphic yeasts
Haptens
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LCM
Fungi
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Mycobacteria, Listeria, Yersinia
Oils of insecticides, plasitics, metals, etc
Allograft MHC molecules
Neoplastic cell antigens
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Granulomatous inflammation
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