Exam 2 (L17-23)

What is immunity vs. hypersensitivity?

Immunity → beneficial immune response

Hypersensitivity → immune response is harmful

What immune system is non-specific?

Innate Immunity

What immune system is specific?

Adaptive Immunity

What immune system is present BEFORE infection and is the first line of defense?

Innate Immunity

What immune system creates memory and is the second line of defense?

Adaptive Immunity

How long does innate immunity take to respond?

Minutes to hours

What types of cells are involved in innate immunity?

1. Phagocytic Cells (neutrophils and macrophages)

2. NK Cells

3. DCs

What receptors are activated in innate immunity and what sigials do they recognize?

PRRs (pattern recognition receptors) → recognize PAMPS and DAMPS

TLRs → recognize PAMPS and signal to host there’s an infection

What are PAMPS?

Pathogen Associated Molecular Patterns

Located on infectious organisms and are recognized by leukocytes and epithelial cells

What are DAMPS?

Damage-associated molecular patterns

Endogenous molecules from within the cell that are released when the cell is damaged or during inflammation

What are the 3 locations of PRRs?

1. Transmembrane

2. Cytosolic

3. Secreted (extracellular) → in a endosome inside the cell

What are TLRs?

A type of PRR located on the cell surface and in endosomes

What do TLRs recognize from gram + and negative bacteria, viruses and fungi?

• LPS from gram - bacteria

• Peptidoglycan from gram + bacteria

• dsRNA from viruses

• Alpha-glucan from fungi

What TLRs detect bacteria?

1, 2, 4

What TLRs detect viruses?

3, 7, 8, 9

What are NLRs?

Cytoplasmic receptors that recognize different molecules that activates the inflammasome and induces production of IL-1 (signals leukocytes to inflammatory site)

What activates the inflammasome?

NLRs or LPS binding to TLR4

How long does it take for an adaptive immune response?

Days to weeks

What are B lymphocytes and what do they fight?

• Process Ab for Humoral Immunity

• Fights extracellular pathogens and toxins

What are T lymphocytes?

• Cytotoxic and Helper Cells for Cell-mediated immunity

• Fights against intracellular pathogens

What allows the adaptive immune system to distinguish between foreign and normal cells?

MHC System → T lymphocytes usually only recognize an antigen if they’re bound to MHC molecules (“MHC restriction”)

• MHC bind peptide fragments of foreign proteins to present to antigen-specific T cells (they’re like the fork/spoon for the T cells)

The MHC system is important in ______ and ______ immunity.

humoral and cell-mediated

What is MHC Class I?

• Present in nucleated cells

• Presents peptide Ag to CD8 (Cytotoxic T)

• Not as restrictive as Ab and TCRs

What is MHC Class II?

• Tissue distribution varies

• Induces CD4 (T helper cells)

• Typically are exogenous antigens that have been processed in endosomes and lysosomes of APCs

What MHC regulates T lymphocyte development? Where does this occur?

MHC II → thymus and peripheral LN

What does MHC influence clinically?

• Transplate acceptance or rejection

• Immune responsiveness

• Pathogenesis of many diseases

Where are T lymphocytes made?

Made in bone marrow and then migrate to the thymus → leave as effector lymphocytes

What is present on T cells that allows them to recognize antigens?

TCR

__________ are used as diagnositic tools ot identify neoplastic and nonneoplastic lymphocyte populations.

IHC markers

What is the funciton of CD8+?

• Recognize infected cells that contain microbial antigen

• Initiate cell killing.

What is the funciton of CD4+?

Recognize microbial Ag in phagocyte → triggers release of cytokines → activate macrophage → initiate inflamation → stimulate B cells

• Needs to be fed

If the APC cannot bind to CD28 on the T cell, what happens?

Apoptosis

How are T cells activated?

1. TLR/MHC Ag complex binds to appropriate TCR

2. CD80 or CD86 on the APC binds to CD28 on T cell

3. Clonal expansion of that T cell with the same Ag-specificity

What regulates T cell activation?

1. Treg

2. Cytotoxic T lymphocyte associated protein 4 (CTLA-4)

What are Tregs?

• Distinct CD4+ Cells that inhibit self-reactive CD4 lymphocytes that escaped the negative selection process in the thymus (ie. thymus is suppose to get rid of self-reactive helper cells, but these ones escaped)

What do Tregs help prevent?

• Prevents organ-specific autoimmune disease

• Oversees immune responses to microbial pathogens → prevents too much inflammation

What are the two phases of B lymphocytes development?

1. Antigen-Independent Phase → primary lymphoid tissues (bone marrow, thymus)

• Don’t need Th cells → antigen activates it itself

• Express IgM and IgD on their surface → signals for cell to mature

2. Antigen-Dependent Phase → mature cells, secondary lymphoids tissues (spleen, LN)

• Need Th cells to help differentiate into mature cells

• Ag-activated, mature B cells differentiate into either IgM-secreting plasma cells or switch to another Ab isotype

How to B Cells mature?

1. CD40 on B cell binds with CD40L on T Helper Cell (CD4)

2. Binding allows B cell to become an Ab-secreting plasma cell and memory lymphocytes that can recognize the same Ag

What prevents B lymphocytes from isotype switching to a different Ab? What does this result in?

Failure of T cells to express CD40L → hyper-IgM syndrome

What mechanism destroy the target cell when Ab bind to Ag and what cells are they associated with?

1. Ab-dependent cell-mediated cytotoxicity → mediated by NK cells

2. Phagocytosis → mediated by monocytes (circulation) and Macrophages (tissue)

3. Complement-Dependent Cytotoxicity (CDC) → MAC Formation

What do macrophages do?

• Phagocytosis → main role

• Antigen Presentation (APC): phagocytoses antigen → processes into peptide fragments → presents to T cell

• Cell-Mediated Immune Response (Type IV hypersensitivity reactions)

What type of hypersensitivity do macrophages pay a role in?

Type IV

What cells types are MHC II presenting?

• Macrophages

• B Cells

• DCs

What are dendritic cells?

• Process antigens and present them to T Cells (APCs)

• Help in negative selection in the thymus → prevent self-recognition lymphocytes from being released

• Maintain peripheral tolerance

What are NK Cells?

Nonspecific cytotoxic cells that respond to tumor cells and viral infections

What to NK cells contain in their cytoplasm?

Cytotoxic granules → perforin and granzymes

• Help to lyse target cell

Unlike cytotoxic T cells, NK cells are __________, ________ and _____ develop memory cells.

Not MHC-restricted, cytolytic, do not develop memory cells

What do hypersensitivity reaction require?

A sensitization phase → host must become sensitized to that specific antigen

1. Previous exposure

2. Prolonged exposure

What are teh most common harmful effects of the effector phase of hypersensitivity reactions?

Inflammation and/or cell lysis

What hypersensivities are antibody vs. cell mediated?

Type I-III → antibody

Type IV → cell

What are Type I Hypersensitivity?

“Immediate Hypersensitivity” (Systemic vs. Localized)

• Triggered by the binding of antigen to IgE antibody on the surface of mast cells → allergic reactions

• Antigens (allergens) include: pollen, parasites, insect venom proteins etc.

_____ is needed in Type I Hypersensitivity reactions so that B cells can switch their class to IgE.

IL-4

What is the two phases of Type I Hypersensitivity reactions?

1. Sensitization Phase → host develos antigen-specific IgE response when it first meets the antigen

• Th2 and B Cells help make IgE → IgE binds to Fc receptors on mast cells (most important) and basophils (“mast cells are prepped for war and are advised on who their enemy is”)

2. Effector Phase → cross-linking of two or more IgE on the mast cells → cell release of mediators (degranulates) → causing inflammatory reaction

What are the three responses in Type I Hypersensitivity reactions and what cells are associated with each?

1. Acute Inflammatory Response → depends on resident mast cells

2. Late-phase response → recruited cells (especially eosinophils)

3. Chronic inflammatory response → prolonged exposure, recruited cells (especially eosinophils)

What is being shown on this histology slide and what hypersensitivity reaction is most likely associated?

Mast Cells → nucleus is obscured by basophilic granulation

Type I

How are mast cells activated in Type I Hypersensitivity reactions?

• Cross linking of membrane-bound IgE by antigen

• Cytokines → IL-8

• Complement Products

• Drugs

• Physical stimuli like heat, cold, trauma etc.

Anaphylaxis is a Type I Hypersensitivity reaction that occurs _______.

systemically

Where do localized Type I Hypersensitivity reactions occur and what are the associated clinical diagnoses?

Epithelial surfaces → skin, respiratory, GIT

• Allergic dermatitis → cutaneous manifestation

• Dietary → cutaneous or GI manifestation (dogs and cats)

• Flea and other arthropod bites → cuteanous manifestation (hives)

All Type I Hypersensitivity diseases are characterized by ______ inflammatory reactions that are caused by ___________.

acute, mediators released from sensitized mast cells

What occurs in acute inflammation of Type I Hypersensitivity reactions?

Mast Cells degranulate → release vasoactive amines → increases blood flow, vascular permeabilityy and causes smooth muscle spasms → additional leukocytes (especially eosinophils) are recruited and release substances that cause more cell damage → epithelial cells are activated produce factors that activate additional inflammatory cells

Anaphylaxis is a reaction to an antigen that results in a _______ state and often involves ___________.

shock-like, multiple organ systems

What are the primary target tissues of anaphylaxis?

Blood vessels and smooth muscles

What are the early signs of anaphylaxis? What can cause a patient to die from it?

Early: cutaneous (swelling, itching, hives), cardiovascular, respiratory

Can be fatal by causing asphyxiation secondary to edema of the upper airway, circulatory failure (too much dilation of splachnic vascular blood) or hypoxemia due to severe bronchospasms

What are the pathognomonoic lesions of anaphylaxis?

There are none because it’s systemic, but there can be lesions like edema, pruritis, dyspnea etc. they’re just not pathognomonoic

What are teh shock organs of most animals, dogs and cats?

Most → lungs

Dogs → liver

Cats → GIT

What are Type 2 Hypersensitivity reactions?

When antibodies are made against antigens on the surface of a cell or tissue resulting in destruction

What are endogenous vs. exogenous antibodies directed at in Type 2 Hypersensitivity reactions?

Endogenous Ab → self-antigens (autoimmune responses)

Exogenous Ab → foreign antigens

What is ADCC and what cells are involved?

Antibody-dependent cellular cytotoxicity

• Pathogen is opsonized (tagged) with an antibody for phagocytosis

• Macrophages, NK Cells, Neuts and Eosinophils → have FcR for the Ab on the pathogens

What is the complement system response in Type 2 Hypersensitivity reactions?

• Antibodies that have an antigen bind to FcR on leukocyte → activates complement system

  • Releases C5a and C3a → secondary inflammation by recruiting inflammatory cells

  • Releases C3b → opsonizes the target → phagocytosis

  • Formation of MAC → cell lysis

How does Type 2 Hypersensitivity affect receptors?

Antibodies disturb normal functioning of receptors → either act as agonists or antagonists → results in altered cell/tissue function

What’s an example of antibody-mediated reponse against receptors in Type 2 Hypersensitivity reactions?

Myasthenia Gravis → Ab block AchR → causes muscle paralysis and weakness

What are some examples of Type 2 Hypersensitivity reactions against erythrocytes?

• Neonatal Isoerythrolysis

• Transfusion Reactions

• IMHA

• Drug induced hemolysis → alters RBC membrane

• Infectious diseases (anaplasma, EIA) → antigens adhere to RBCs

What are some examples of Type 2 Hypersensitivity reactions against platelets?

Immune mediated thrombocytopenia (IMT) → can be autoimmune or drug-induced, alters platelet membrane

Some clincial signs of IMT include ______ and ________.

Petechiae, purpuric hemorrhage

What are some examples of Type 2 Hypersensitivity reactions against dermal cells?

Pemphigus disease complex → antibodies go against desmosomal proteins that keep keratinocytes together → causes transient vesicle and bullae formation (space between keratinocytes)

What are Type 3 Hypersensitivity reactions?

Formation of Ag-Ab complexes that activate the complement system and cause tissue damage as a result

What antibodies are most commonly involved in Type 3 Hypersensitivity reactions?

IgM and IgG

What determines the pathogenicity of Type 3 Hypersensitivity reactions?

Size of immune complex

• If antibody is much bigger than Ag → large and insoluable, easily removed by phagocytosis

• If antigen is much bigger than Ab → overall small, travel freely

• If they’re equal in size or if Ag if slightly bigger → complexes lodge in tissue → activate complement → necrosis (blood vessels, synovial membranes, glomeruli, choroid plexus)

What can Type 3 Hypersensitivity reactions cause in blood vessels?

Coagulative Necrosis

What can Type 3 Hypersensitivity reactions result from?

• Persistent infections

• Autoimmune Dz

• Inhalation of foreign antigen

How does Type 3 Hypersensitivity reactions cause cell damage?

Fc segment of antibody activates complement and leukocytes → damages to cell and adjacent tissue (innocent bystander) at site of deposition

What are the phases of Type 3 Hypersensitivity reactions?

1. Ab form comlexes with intravascular Ag

2. Immune complexes are deposited in blood vessels of tissues

3. Complement and neutrophil-mediated damage to tissue

4. Macrophages are recruited → produce pro-inflammatory cytokines

What’s an Arthus Reaction?

Type 3 Hypersensitivity reaction that causes a localized area of tissue necrosis resulting from necrotizing vasculitis → complexes are depositing in vascular tissue and causing the surrounding tissue to die

What causes canine “blue eye?”

Adenovirus Type I

Inflammation of anterior chamber of the eye causes damage to corneal endothelium → corneal edema → Type 3 Hypersensitivity reactions

________ occurs to a degree in all Type 3 Hypersensitivity reactions.

Vasculitis

What does vasculitis from Type 3 Hypersensitivity reactions look like on histology?

Fibrinoid necrosis with neutrophil infiltration

What does FIP look like grossly and histologically?

It’s a Type 3 Hypersensitivity reaction

• Vasocentric infiltration by macrophages and neutrophils (they center around teh vessels) with vasculitis

Describe how renal immune complexes occur in Type 3 Hypersensitivity reactions and what can cause them.

Immune complexes depositin in the glomerulus, causing glomerulonephritis

• Viral: EIA, feline leukemia, FIP

• Bacterial: pyometra (dogs), endocarditis

• Parasitic: HW

What can highlight immune complexes in the glomeruli?

PAS stain → very eosinophilic

Immuno-fluorescence → bright green

What are some diseases associated with Type 3 Hypersensitivity reactions?

• SLE

• Blue Eye

• EIA

• Cuteanous vasculitis

• Glomerulonephritis

• Reactive arthritis

• Rheumatoid Arthritis

• Arthus Reactions

• Serum Sickness

• COPD

• Hypersensitivity pneumonitis

What are Type 4 Hypersensitivity reactions?

Delayed, cell-mediated hypersensitivity that results from T lymphocytes that are sensitized to a specific antigen

What are the two different immune response of Type 4 Hypersensitivity reactions?

1. Direct cytotoxicity (CD8+) → APC binds to CD8 → causes direct cellular injury together

2. Delayed Hypersensitivity (CD4+) → APC binds with CD4 → Release of cytokines that act through macrophages to produce chronic inflammation → then causes cellular injury

Type 4 Hypersensitivity reactions are typically _______, as they are reactions to _______ antigens.

chronic, persistent

What is the tuberculin response?

A Type 4 Hypersensitivity reaction associated with an intradermal injection of tuberculin antigen → previously sensitized host will have a localized reaction

What is erythemia multiforme?

A Type 4 Hypersensitivity reaction against the antigens on the surface of keratinocytes → CD8+ target keratinocytes → apoptosis

What is contact dermatitis?

A Type 4 Hypersensitivity reaction where chemical substances (ex. flea tx) bind to cell associated proteins → then are targeted by CD8+

What is granulomatous inflammation and what causes it?

A Type 4 Hypersensitivity reaction where a persistent antigen cauess a granulomatous and lymphocytic inflammation (lots of macrophages, giant cells, necrosis and fibrosis)

• Caused by BACTERIA → mycobacterium, arcanobacterium, brucella

• Fungi and some parasites

What are some examples of Type 4 Hypersensitivity reactions?

• Tuberculosis

• Allergic contact dermatitis

• Rheumatoid arthritis

• Johne’s Dz

• Allograft rejection

• Equire recurrent uveitis

Immunodeficiencies occur when there is a failure of the immune system to protect the host from _________ or _______.

infectious agents, cancer development

Differentiting between primary and secondary immunodeficiency is crucial for _______ and _______.

treatment, prognosis