Flashcards in Disease of Immunity Deck (97):
Innate immunity is present in what organisms? What is the speed and specificity of the response?
All multicellular organisms and it is fast but not specific
Adaptive immunity is present in what organisms? What is the speed and specificity of the response?
It is in higher vertebrates and is slower but more specific due to memory
Innate immune system includes ______________ and activation of cells that induce an _________________________.
physical barriers like GI skin and respiratory tract and cells that induce inflammation via the release of cytokines, chemokines and acute phase proteins
In the innate immune response, acute-phase reactants like ______________ help promote phagocytosis and killing of pathogens.
What cells are involved in the adaptive immune response?
What types of immunity do they provided?
T and B cells
They provide humoral immunity via circulating Ab and cellular immunity via cell-to-cell contact and or cytokine activity in a cellular microenvironment
T lymphocytes originate in the _________ and differentiate in the ________.
Originate in bone marrow and differentiate in the thymus
Helper T cells are characterized by the presence of ____________ and cytotoxic T cells are characterized by the presence of _______.
Helper T= CD4
Cytotoxic T = CD8
CD4 recognizes MHC class _____ while CD8 recognizes MHC class_______.
What percentage of circulating lymphocytes are T cells? B cells? NK cells?
B cells are 10-20%
NK = 10-15%
T cells recognize ___________ on cells while B cells recognize_________________.
Which recognizes a wider variety of substances?
T cells recognize peptides presented in MHC
B cells recognize antibodies bound to antigens.
B cells recognize a wider variety of substances because the antigen can be peptide, lipid, polysaccharide, nucleic acid, etc
What tissue have dendritic cells (DC)? What is their function?
Lungs and skin and they are :
2. express low levels of MHC/co-stimulatory molecules
This allows them to process antigens and deliver them to the spleen and lymph nodes where they are MHCII presenters
What is the function of NK cells?
They lack T cell receptors and Ig but they have Fc receptors to provide non-specific cytotoxic activity toward virally infected cells
NK cells have both _____ and ______ receptors that recognize a variety of ligands including ________ which is important for recognizing self from non-self.
Activating and inhibitory receptors and recognize HLAC which distinguishes self from non-self
What is a gamma delta T cell?
T cell associated with mucousal surfaces recognize NON-PROTEIN molecules like bacterial lipoglycans
Innate and adaptive
Basophils and mast cells have high affinity receptors for ______ and upon crosslinking will release ______, ______ and ______ that mediate __________.
IgE and will release heparin, histamine, and other effector molecules that mediate allergic response
What are the first line of defense phagocytic cells?
When they phagocytose they are activated to secrete cytokines to promote inflammation
What do TLRs recognize extracellularly?
What do they recognize intracellularly?
PAMPs (pathogen associated molecular patterns) that recognize bacteria, fungi and parasite-derived ligands
Intracellular recognize bacteria or viral nucleic acid
TLR signal through _____ or ______ to do two things. What are those two things?
They signal through MyD88 or TRIF and they:
1. release cytokines
2. upregulate MHC and co-stimulatory molecules (CD80/86)
TLR--> MyD88--> IRAK4--> TRAF6--> ___________________________
Transcription factors like NF-kB
What makes TLR different from the recognition used by the adaptive immune system?
T cells and B cells recognize pathogens using a receptor encoded by rearranged genes (they have much higher specificity for pathogens)
T cell activation requires 3 signals. What are signal one and two and three?
1. Recognize peptide in MHC by the T cell receptor
2. CD28 on the T cell is costimulated by CD80/86 on the surface of the APC
3. IL-2 is released to propagate the response
What happens if a T cell receives signal one (the MHC presented antigen) but NOT signal two (CD28 binding to CD80/86)?
It will result in anergy (non-functional T cell)
What are the steps in B cell activation?
1. Binding of antigen to a surface bound antibody
2. CD40 on B cell binds CD40L on T cell
(The T cell can recognize MHC on a B cell so they stimulate each other)
What are the three main subsets of helper T cells?
What does each produce and what is the function?
Th1- produces IFNg to activate macrophages and Ab producing B cells
Th2- produces IL4 which stimulates B cells to class-switch and differentiate into IgE plasma cells
Th17- IL17 which is a key inflammatory cytokine
How does IFNg play a role in immune response?
What Th cell produces it?
IFNg will activate macrophages and Ab producing B cells
It is made by Th1
What role does IL4 play in immune response? What Th cell produces it?
It makes the B cell class switch and differtiate into IgE producing plasma cells
What role does IL17 play in immune response? What Th cell produces it?
It releases inflammatory cytokines and is made by Th17
What cells can display MHCI or HLAI? Why is this important?
What cells display MHCII?
All cells can display MHCI so cytotoxic T cells (CD8) can recongize virally infected cells and release granzyme and perforin to kill them
APCs display MHCII to activate T cells
What are ways Ab participate in the immune response?
1. neutralize microbes and toxins
2. opsonize by binding to pathogen and Fc receptors on phagocytic cells
3. Induce degranulation by binding Fc
4. IgM, IgG1, IgG3 can induce complement cascade to form a MAC complex to lyse the target cell
What three Ig can form MAC complexes and start a complement cascade?
IgG1, IgG3 and IgM
How does a normal immune response end?
The majority of lymphocytes die by apoptosis once the pathogen has been removed
The few remainders become long-lived memory cells which can survive for weeks and respond to "known pathogens"
What are the four major hypersensitivities?
1- immediate (allergic response)
3. Immune complex mediated
4. T cell mediated
What initiates type one hypersensitivity?
The binding of antigen specific IgE to mast cells or basophils
Exposure to ________ or ____________ that lead to the development of IgE secreting plasma cells is characteristic of a type 1 hypersensitivity.
recall antigen or immunologically similar epitopes
Type1 response occurs in what time frame? On what exposure?
Within minutes of re-exposure (the first exposure makes the IgE antibodies to the hapten allowing a strong Th2 response).
What Th type plays a large role in type 1 hypersensitivity?
Th2 because it secretes IL4 which class-switches B cells to IgE plasma cells
What is the sequence of events in a type 1 hypersensitivity reaction?
1. Th2 activates and produces IgE Ab
2. Th2 produces IL4. IL5, IL13
3. IgE binds to Fc receptor on mastcell/baso/eosinophil
4. activation and release of histamine, heparin etc
What three IL are released in a type one sensitivity reaction? What does each do?
IL4- class switching to IgE
IL5- activates eosinophils
IL13- acts on epithelial cells to stimulate mucus secretion
What three groups of mediators are released from mast cells in a type 1 hypersensitivity reaction?
1. vasoactive amines- histamine, adenosine, chemotactic factors, proteases, proteoglycans
2. lipid mediators- prostaglandins, LK
3. Cytokines- TNF
What are the five major vasoactive amines released from mast cells? What does each do?
1. Histamine- vasodilation and increased vascular permeability, mucus secretion
2. Heparin (proteoglycan)
3. Chemotactic factors- attract eosino/baso
4. Adenosine- bronchoconstriction and inhibits platelet aggregation
5.Proteases which damage tissue
What are the two stages of type 1 hypersensitivity reactions? What occurs in each?
1. Immediate/early- within minutes of exposure due to the release of mediators from mast cells and basophils
2. Late phase- 4 to 8 hours later due to the effects of leukocytes involved in the response
What is it called if an immediate/early response of type 1 hypersensitivity is life threatening?
What is atopy?
Familial disposition to type 1 reactions
Anaphylactic shock is usually caused by what type of allergen?
Ingested or injected (rarely inhaled/environmental)
Type 2 hypersensitivity reactions are caused by:
the binding of Ab to cell components or tissues
What are the three ways by which type II hypersensitivity occurs?
1. opsonization and phagocytosis
3. Ab-mediated cellular dysfunction
What are 3 examples of situations where type II hypersensitivity carries out opsonization and phagocytosis?
If RBC or platelets are coated with Ab, opsonized, phagocytosed and eliminated in the spleen
1. Autoimmune hemolytic anemia
2. Autoimmune thrombocytopenia purpura
3. Rh factor
What is the major type II hypersensitivity that causes inflammation?
Goodpasture's syndrome where Ab are made against the BM of kidneys where they bind and activate the complement pathway leading to injury
What are 2 examples of type II hypersensitivity where Ab cause cellular dysfunction?
1. Myasthenia gravis- Ab against nicotinic receptors at the NMJ causing loss of function
2. Graves- Ab that cause hyperthryroidism and gain of function
Type 3 hypersensitivity is characterized by:
deposition of immune complexes in blood vessels or tissue resulting in inflammation
What is the 3 phase process by which type 3 hypersensitivities develop?
1. Antigen-Ab complex forms
2. Deposition in vessels
3. Inflammatory response at various systemic sites
What are three examples of type III hypersensitivities?
1. systemic lupus erythomatous
2. serum sickness
3. polyarteritis nodosa
How does the size of the immune complex correlate to the pathogenicity?
Large complexes can be removed by macrophages via binding to free Fc regions
Small and intermediate complexes occur when there is antigen excess and are harder to clear
What do you have in excess if large immune complexes form?
What do you have in excess if small immune complexes form?
What are the most common sites of deposition of immune complexes in type III hypersensitivity?
1. kidneys (glomerularnephritis)
2. joints (arthritis)
3. small blood vessels (vasculitis)
What is an Athus reaction?
When Ab-antigen complexes form resulting in local vasculitis.
This occurs with injectable antigens like diptheria and tetanus toxoids
It results in swelling, edema, hemorrhage, necrosis
T cell mediated hypersensitivity is type _____. What two ways does it cause damage?
1. CD4 recognizes an antigen on MHCII and makes cytokines mediating inflammation
2. CD8 recognizes MHCI and kills the cell
Delayed Type Hypersensitivity (DTH) is a recall response that occurs _____ to _____ hours after an antigenic challenge.
12 to 48
Unlike type I hypersensitivity that includes ________ and _____Cells and occurs _________, the type 4 DTH include _______ cells and occur on a ________ time scale.
Mast cells and basophils and occur rapidly (type I)
DTH has T cells and occurs on a slower time scale
What are two good examples of DTH?
1. TB skin test in previously exposed individuals
2. Contact dermatitis
What Th mediates type I hypersensitivity reactions?
What Th mediates type IV?
I- Th2 which releases IL4, IL5, IL13
IV- Th1 which releases IFNg to activate macrophages
What is the major example of CD8 T cell mediated killing of "self" cells in type 4 hypersensitivitY?
What is central tolerance?
Where does it occur for T cells? B cells?
Selection of T or B cells that are unresponsive to self-antigens during the maturation process
T cells in the thymus B cells in the bone marrow
How does T cell central tolerance work?
T cells are presented with self MHC and self antigen. If they bind too tightly, they are killed by apoptosis
What is peripheral tolerance?
The self-reactive T and B cells that escaped central tolerance are subject to peripheral "checks"
2. Regulatory cells
3. activated-induced cell death
What is anergy?
IF a T or B cells receives signal one but not the co-stimulatory activation signal, they will become inactive
Treg are characterized by surface expression of ______ and intracellular expression of _______ that can suppress immune response.
surface expression of CD25 and inhibitory ligand for CD80/86
Intracellular expression of FOXP3
What does Treg secrete to damp down immune response?
TGF-b and IL10 which are immunosuppressive
AICD (activation induced cell death) is caused by ______________ .
apoptosis of activated immune cells via receptor/ligand binding
What is the most common trigger of AICD>
What are the three requirements for suspecting an autoimmune disease?
1. targeting of self-antigen
2. Primary reaction (no prior exposure necessary or no tissue damage)
3. other causes ruled out
What are the four common causes of autoimmunity?
1. mutations of genes involved in tolerance
2. genetic predisposition
3. molecular mimicry
What are 2 examples of mutations of a genes involved in tolerance?
1. Fas mutation will reduce activation-induced cell death (AICD) and will result in autoimmune lymphoproliferative syndrome
2. AIRE mutation in central tolerance causes autoimmune polyendocrine syndrome
What genetic predisposition is associated with rheumatoid arthritis?
What is molecular mimicry?
Bacteria/viruses yield immune responses that are cross-reactive with self antigens
What are environmental causes of autoimmunity?
UV radiation, drugs, smoking and citrulin
Lupus is an autoimmune disease characterized by the production of _________ to ________.
Who does it usually infect?
IgG antibodies to nuclear constituents
It usually affects women of childbearing age
What are the clinical presentations of Lupus? What is the telltale sign?
Fever, fatigue, anorexia/weightloss
Malar butterfly rash is the well-known sign
What are the skin manifestations of lupus?
Malar rash, discoid lesion, alopecia
What are the musculoskeletal effects of SLE?
joint pain and arthralgia or arthritis
What are the kidney problems associated with SLE?
50% of lupus patients have hematuria, proteinuria, and impaired creatinine clearance (decreased GFR) due to deposited immune complexes
What hematological effect is noted with SLE?
Anemia occurs due to systemic inflammation
Leukopenia due to anti-lymphocytic Ab
What are the autoantibodies directed against in SLE?
1. nuclear and cytoplasmic components
2. Cell surface antigens (lymphocytes, RBC, platelet)
3. Phospholipids causing thrombosis
What is the main mechanism of tissue injury in SLE?
Immune complexes deposit and cause organ damage (type 3 hypersensitivity)
What is lupus anticoagulant?
Lupus will be anti-coagulant in vitro but coagulant in vivo
What is rheumatoid arthritis and what is the definitive test to ID RA patients?
It is when chronic joint inflammation leads to destruction of tissue cartilage
Anti-CCP test determines RA patients
What is Sjogren syndrome?
Who does it typically affect?
Autoimmune disease characterized by dry eyes and mouth due to lacrimal and salivary gland destruction.
It affects women between 35-45
Antibodies associated with Sjorgrens syndrome are directed to _____ and _____ and Fc component of _______.
SS-A and SS-B and Fc components of IgG (Rheumatoid factor)
What is scleroderma?
Who does it affect?
What are the two subsets?
A disorder characterized by excessive fibrosis of tissues and production of autoantibodies.
It affects women 50-60.
1. Limited cutaneous systemic sclerosis
2. Diffuse cutaneous systemic sclerosis
What is limited cutaneous systemic sclerosis?
Scleredoma of face, neck and extremities.
Patients with CREST
What is CREST?
What is the discriminating clinical feature?
What are Ab directed against?
R - Reynaud's
E - espophageal dysmotility
S - schlerodactyly
T - telangiectasis
Discrimintation feature is sclerodactyly (fibrosis of fingers)
Ab directed against centromeres
What is diffuse cutaneous systemic sclerosis?
trunk and extremities wher the skin thickens and is accompanied by fatigue, anorexia, weight loss, cardiac hypertrophy
What are Ab directed against in limited scleroderma?
What are Ab directed against in diffuse scleroderma?
Diffuse = topoisomerase I and RNA pol III
What group of ppl have the highest incidence of scleroderma?
Choctaw Native Americans because of autoantibody against fibrillin-1
What is the sequence of progression in scleroderma?
1. Injury to endothelial cells
2. T cells respond to self-antigens and produce cytokines that activate fibroblasts and collagen production
3.fibrosis leads to ischemic injury
4. B-cells produce ANA against DNA topoisomerase I and anti-centromere Ab