Cormac Immunity Lectures Flashcards
What disease is Candida albicans associated with?
Fungal pathogen associated with Thrush
What disease is Yersinia Pestis associated with?
Black death
Who does Pseudomonas aeruginosa impact?
Only causes disease in immunocompromised
How does cancer immunotherapy work?
Cancer cells express molecules they shouldn’t. Immune system should recognize and destroy. Some cancers produces PDL1 which cloaks themselves. Immunotherapy can ‘decloak’ cancer cells allowing bodies immune system to destroy
-what does -itus mean for disease?
Inflamatory response
Identify the Immune Cells
Identify Cells of the Innate and Adaptive Immune System
Location of B-cell Development?
Bone Marrow
Location of T-Cell Development
Thymus
5 General Principles of Immunity
Prevention before removal.
Expansion and migration of immune cells to site of action.
Killing of pathogen or infected cells.
Cleaning up afterwards.
Memory for future protection.
Examples of Innate Immune Cells?
Physical / Chemical Barriers
NK cells
Macrophages
Neutrophils
Dendritic cells
Examples of Innate Immune Cells?
Physical / Chemical Barriers
NK cells
Macrophages
Neutrophils
Dendritic cells
Examples of Adaptive Immune Cells
Antibodies
T & B lymphocytes
Dendritic cells
Role of TLR In immunity
Resident cells have TLR (tole like receptors) expressed on most cells
Germline-encoded recognize patterns expressed on bacteria
Physical Barriers of Innate Immunity
Goblet cell mucous secretion
Acid of stomach kills most bugs
Salt from sweat washes away bacteria, less friendly for pathogens
Role of NF- Kappa B in Immunity
Part of Innate Immune response
transcription factor that drives expression of hundreds of genes protecting against that particular invader
Encourages phagocytosis from innate immune cells (macrophage and dendritic)
Role of Chemokines and Histamine in Innate Response
Released in a gradient to attract Neutrophils and expresses adhesion proteins in endothelium
How can Neutrophils attack invaders?
Invaders can be phagocytosed, spew chemicals onto the invader, or neutrophil net. Squeeze neutrophil that ejects DNA net that traps invaders in its stickiness
Natural Killer Cells in Immune response. Innate or Adaptive?
Part of Innate Immune response. Lymphocytes that recognize any cell that has lost MHC I and kill them. Cells that are infected/ tumors don’t express this and are killed
What is self-reactive lymphocytes removal is called?
Tolerance
What do Activated B-Cells produce?
Activated B-cells produce antibodies
What do activated T-Cells Produce?
Activated T-cells produce cytokines and kill infected cells
Antigen-specific lymphocytes enter into the circulation and “visit” the ________ and ____________ tissues
When a clone is presented with its ____________, it expands and re-enters the
circulation.
Antigen-specific lymphocytes enter into the circulation and “visit” the lymph nodes and secondary lymphoid tissues
When a clone is presented with its cognate antigen, it expands and re-enters the
circulation.
How Dendritic cells present Antigens
What happens when antigen is presented by Dendritic Cells to T-Cell?
Occurs in the Lymph Node. Lymphocytes will become antigen-specific, expand and Re-enter the circulation seeking out their cognate antigen.
Steps of Inflammation Response
- Damaged Tissues release Histamines increasing blood flow to the area
- Histamines cause capillaries to leak releasing phagocytes and clotting factors into the wound
- Phagocytes engulf bacteria, dead cells, and cellular debris
- Platelets move out of capillaries and seal wounded area
Role of Mast Cells in Inflamation
- Mast cells secrete factors that mediate vasodilation and vascular constriction delivering more blood and plasma
Macrophages Role in Inflammation and Immune Response
- Phagocytose pathogens
- Also, secrete Cytokine hormones that attract immune cells to the site and activate tissue repair
Neutrophil role in Inflammation and Immune Response
- Phagocytose pathogens
- Secrete factors that kill and degrade
Mechanisms of Cytokine release
Epithelial Cells:
- Provides barrier function through tight junctions.
- Produces ___________ peptides and mucous.
- ______ antigen-presenting cells.
- ______ responsiveness to TLR ligands.
- Generally _____ phagocytic activity.
Epithelial Cells:
- Provides barrier function through tight junctions.
- Produces antimicrobial peptides and mucous.
- Not antigen-presenting cells.
- Low responsiveness to TLR ligands.
- Generally low phagocytic activity.
______________:
- Phagocytic and professional antigen-presenting cell.
- Activated by TLR engagement.
- Multiple subtypes exist.
- Characterized by high surface area.
- Generally low phagocytic activity.
Dendritic Cell
- Phagocytic and professional antigen-presenting cell.
- Activated by TLR engagement.
- Multiple subtypes exist.
- Characterized by high surface area.
- Generally low phagocytic activity.
__________________:
- Professional Phagocytic and Antigen-presenting cells.
- Activated by TLR engagement.
- Multiple subtypes exist.
- Generally high phagocytic activity.
Macrophage:
- Professional Phagocytic and Antigen-presenting cells.
- Activated by TLR engagement.
- Multiple subtypes exist.
- Generally high phagocytic activity.
__________________:
- Least common type of WBC.
- Phagocytic.
- Produce inflammatory mediators.
- Particularly high in parasitic infections.
- -Activated by the presence of IgE antibosies
Basophils
- Least common type of WBC.
- Phagocytic.
- Produce inflammatory mediators.
- Particularly high in parasitic infections.
- -Activated by the presence of IgE antibodies
__________________:
- Least common type of WBC.
- Phagocytic.
- Produce inflammatory mediators.
- Particularly high in parasitic infections.
- -Activated by the presence of IgE antibosies
Basophils
- Least common type of WBC.
- Phagocytic.
- Produce inflammatory mediators.
- Particularly high in parasitic infections.
- -Activated by the presence of IgE antibodies
__________________:
- Common in allergic inflammation.
- Reside in tissues.
- Produce inflammatory mediators.
- High in parasitic infections.
- -Activated by the presence of IgE antibodies
- Common in allergic inflammation.
- Reside in tissues.
- Produce inflammatory mediators.
- High in parasitic infections.
- -Activated by the presence of IgE antibosies
__________________:
- Common in allergic inflammation.
- Granules with Histamine and heparin.
- Produce inflammatory mediators.
- Similar in appearance and function to basophil.
- Activated by the presence of IgE antibodies
Mast Cell:
- Common in allergic inflammation.
- Granules with Histamine and heparin.
- Produce inflammatory mediators.
- Similar in appearance and function to basophil.
- Activated by the presence of IgE antibodies
______________:
- Most abundant type of white blood cell.
- Recruited from circulation via chemotaxis.
- Release cytokines to amplify inflammation.
- High phagocytic activity (opsonized targets).
- Degranulation.
- NET formation
Neutrophil:
- Most abundant type of white blood cell.
- Recruited from circulation via chemotaxis.
- Release cytokines to amplify inflammation.
- High phagocytic activity (opsonized targets).
- Degranulation.
- NET formation
______________:
- Most abundant type of white blood cell.
- Recruited from circulation via chemotaxis.
- Release cytokines to amplify inflammation.
- High phagocytic activity (opsonized targets).
- Degranulation.
- NET formation
Neutrophil:
- Most abundant type of white blood cell.
- Recruited from circulation via chemotaxis.
- Release cytokines to amplify inflammation.
- High phagocytic activity (opsonized targets).
- Degranulation.
- NET formation
Neutrophil Killing Mechanisms
Phagocytosis, Degranulation, NETS
_________________________:
- Nonphagocytic cells.
- Release perforins which lyse target cell membranes.
- Recognises target cells via “missing self” MHC antigens.
Natural Killer Cell:
- Nonphagocytic cells.
- Release perforins which lyse target cell membranes.
- Recognises target cells via “missing self” MHC antigens.
Where do T- cells develop
- T cell precursors from bone marrow migrate to the thymus.
- T cells develop in the thymus developing millions of antigen-specific clones (mature / naïve T-cells)-10K per antigen.
What are T Cells called prior to meeting an antigen? After?
- Before meeting an antigen, they are mature /naïve T-cells
- Antigen presentation results in differentiation into effector T-cells.
Innate/ Adaptive Immunity Overview
MHC Class II on Dendritic Cells Present to which T-Cell Clone?
What Effector Cell does this immature T-Cell become?
CD4+T Cell
Mature Helper T-Cell (Th1 or Th2)
MHC Class I on Dendritic Cells Present to which T-Cell Clone?
What Effector Cell does this immature T-Cell become?
CD8+T Cell
Mature Cytotoxic T Cell (Tc)
Summary of T-Cell Mediated Immunity
Naive T cell recognizes antigen on dendritic cell
results in expansion of that particular clone
CD8+ turned into cytotoxic
CD4+ turned into helper cell
Every cell of the body has MHC Class I or MHC Class II expressed?
What effect does CD8 have?
MHC Class I
Cytotoxic cd8 instruct ell to apoptose
Where do Dendritic cells migrate once they have taken up an antigen?
Dendritic cells take up antigens and migrate to the lymph tissue
What does antigen presentation in the Lymph nodes facilitate?
Antigen presentation by dendritic cells in the lymph node leads to clonal expansion
And the entry of effector (cytotoxic and helper) T-lymphocytes into circulation
What allows B-Cells to recognize antigens?
BCR
What do B-cells require to become Effector B or Plasma Cells
Helper T-cell activation
Where do B cells develop?
Develop in the Bone Marrow migrates to Spleen and lymphoid tissue.
Describe B-Cell Activation
B cell takes up antigen from the bug, presents on MCH II, recognized by T helper cell that secretes cytokines ordering the cell to multiply many times creating a plasma cell that secretes millions of B cell receptor antibodies
Activation of B cell absolutely dependent on helper T- cell for proper function
Where do B cells congregate awaiting presentation of a compatible antigen?
Spleen
Summary of B-Cell Mediated Immunity
How do Cytotoxic Cells function?
Cytotoxic cells seek out cells expressing infection on MHC I triggering their apoptosis
How does immune memory work?
Unresponsiveness to an antigen that is induced by previous exposure to that antigen is known as_______________
Tolerance
What does failure of self-tolerance lead to
Autoimunity
How is self-tolerance achieved
Self-tolerance is achieved by inactivating, killing or
changing the specificity of self-recognizing lymphocytes.
What is the difference between Central and Peripheral Tolerance?
Central Tolerance
T-Cell self-Tolerance
- Occurs in Thymus
- Positive selection (MHC recognizing cells selected for survival).
- Negative selection (removal of self-recognizing T-cells).
B-cell self-tolerance
- Occurs in Bone Marrow
- Removal of self-recognising B-cells by apoptosis (negative selection clonal deletion).
- Second chance for B-cells with low affinity for self (anergy).
Peripheral Tolerance
-Develops after T and B cells mature and enter lymph nodes.
How does Peripheral T-cell tolerance work?
- mediated by T-reg cells. Apoptosis or Anergy (Zombie) state of T-cell
- Dependent upon self-antigen presentation without co-stimulatory molecules or innate immunity.
- Co-receptors: Markers that dendritic cells came from the site of infection. Expressed on the external surface
- If protein reaction occurs in the absence of co-factor, know that component is of self and Tcell and will apoptosis
What is necessary in order to promote clonal expansion and normal t-cell activation?
Antigen Presentation: Peptide presentation on HMC class 1
Costimulation from the site of infection, if absent know that T-cell is self reactive must be killed, or made anergic
4 Potential Outcomes for T cells after entering Thymus
- Exposed to Antigen Presenting Cells, make sure the cell has CD4 or CD8 to bind to MHC and recognize antigens. If not cell apoptosed or made anergic
- Cell recognizes MHC and Self Antigens. These cells are killed by apoptosis, made anergic (zombie) some will turn into anti-inflammatory regulatory T cell
- Lymphocyte that recognizes MHC but no self-antigens. Useful and released into body
- Peripheral Tolerance. If presented to an antigen it binds to, checks for co-receptor
- If presented with antigen by activated DC Clonal Expansion
- Healthy cell without co-receptor. Recognizes it is self reactive cell apoptosis
Are B or T cells able to undergo editing of their receptor if it is self-reactive?
B cells can change of specificity of their receptor by initiating a new round of recombination.
If editing fails, the B-cell will be instructed to undergo apoptosis
How are B cells presented with antigens?
B-cells are not presented antigens by dendritic cells
They are not presented with self-antigens by APCs, just are exposed to their progenitors in the bone marrow
How does peripheral B cell tolerance work?
Mature B cells in the periphery recognizing antigens without T-helper cells will be rendered functionally unresponsive or be instructed to undergo apoptosis
How is a B cell generate antibodies?
- B cell takes up antigen, presents on surface
- T helper cell recognizes an antigen, turns it into antibody producing plasma
- No t-helper cell present, B-cell recognizes it is self-identifying and apoptoses
Presentation of antigen by dendritic cell in thymus versus rest of body?
If antigen presented by the dendritic cell in thymus leads to deletion of T cell
if antigen presented by the dendritic cell in rest of body leads to clonal expansion of T cell
How is primary immunodeficiency diagnosed?
Medical history / physical exam
T cell count / T-cell function
White blood cell count
Antibody deficiency test (IgG, IgA and IgM)
Vaccine response (for a specific antibody)
HIV test
What cells are considered “White Blood Cells”
- Neutrophils
- B Lymphocytes
- T Lymphocytes
- Natural Killer cell
____________________________:
- t-cell development failure leads to failure of activation of b cells
- Diminished antibody response
- Immune system essentially absent
- Mutation in common interleukin component
- Treated with bone marrow transplant
(<3months)
-Current research is investigating gene therapy
Severe Combined Immunodeficiency (SCID):
- Between:
- t-cell development failure leads to failure of activation of b cells
- Diminished antibody response
- Immune system essentially absent
- Mutation in common interleukin component
- Treated with bone marrow transplant
(<3months)
-Current research is investigating gene therapy
Primary versus Acquired Immunodeficiency
Primary
Congenital/hereditary
>80 rare syndromes described
Usually grouped according to the cell type affected
Example: SCID
Acquired
Caused by disease / infection or Drug treatment
More common than PI
Example:
- Immunosuppressive Drugs*
- Malnutrition*
- AIDS*
Primary versus Acquired Immunodeficiency
Primary
Congenital/hereditary
>80 rare syndromes described
Usually grouped according to the cell type affected
Example: SCID
Acquired
Caused by disease / infection or Drug treatment
More common than PI
Example:
- Immunosuppressive Drugs*
- Malnutrition*
- AIDS*
What drugs can cause immunodeficiency?
- Associated with biologic / antibody treatment of inflammatory disease.
- Treatments associated with autoimmune disease, organ rejection, bone marrow transplant, inflammatory disease, chemotherapy
How does HIV incapacitate the immune system?
The virus infects and kills (helper CD4+T-cells, dendritic cells, and macrophages)
What treatment is used for HIV?
Treated with HAART (protease inhibitor): blocks enzyme required by HIV to replicate itself
When do autoimmune conditions usually present?
rarely presents early in life, presents in teens or later. Need environmental trigger to provoke autoimmune disorder
Antibody-mediated Autoimmune Diseases
- Transferable in plasma.
_____________________:
- Target antigen is Red blood cell membrane protein.
_____________________:
- Target protein is in intracellular junctions in the skin.
Myasthenia gravis:
- Target protein is the Ach receptor.
Antibody-mediated Autoimmune Diseases
- Transferable in plasma.
Autoimmune hemolytic anemia:
- Target antigen is Red blood cell membrane protein.
Pemphigus vulgaris:
- Target protein is in intracellular junctions in the skin.
Myasthenia gravis:
- Target protein is the Ach receptor.
Antibody-mediated Autoimmune Diseases
- Transferable in plasma.
_____________________:
- Target antigen is Red blood cell membrane protein.
_____________________:
- Target protein is in intracellular junctions in the skin.
_____________________:
- Target protein is the Ach receptor.
Antibody-mediated Autoimmune Diseases
- Transferable in plasma.
Autoimmune hemolytic anemia:
- Target antigen is Red blood cell membrane protein.
Pemphigus vulgaris:
- Target protein is in intracellular junctions in the skin.
Myasthenia gravis:
- Target protein is the Ach receptor.
Characteristics of T-cell-mediated autoimmune Diseases? Examples?
- Identified by the presence of T-cells in the lesions
- Often very heavily cytokine driven
- Includes Type I diabetes, Rheumatoid arthritis, psoriasis and multiple sclerosis.
What causes Multiple Sclerosis?
- T-cell mediated autoimmunity to myelin.
- Abnormalities in nerve conduction lead to neurological defects
- Cause unknown (maybe viral molecular mimicry with genetic component)
Treatments for Autoimmune Diseases
•Anti-inflammatory Drugs
- Corticosteroids
- NSAIDS
• Immunosuppressants
- Cyclosporine
- Methotrexate
- Plasmapheresis: removes antigen-antibody complexes
- Antibody therapeutics: anti-CD20 (Rituximab), anti-TNFa (infliximab)
- Disease-specific Therapy
