Failures of the Immune System - 6/08

__________________ ____________________ is an epithelial defect where the thymus and a few other structures fail to develop. This means that an individual would be born with no T cells
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__________________ ____________________ is an epithelial defect where the thymus and a few other structures fail to develop. This means that an individual would be born with no T cells
DiGeorge Syndrome
______________________ __________________ ____________________ is when someone has a loss of function or absence of T cells, which means B cell function also becomes impaired. So, cell mediated and humoral immunity are defective
Severe Combined Immunodeficiency (SCID)
If there is a defect in VDJ recombination where the machinery required to stitch V, D and J segments together is faulty then we will have individuals born without _____ or _____ cells
T or B
In a developing B cell, first the _____ and ______ segments combine which is a _____-____ _____________. Then, the _____ segment joins the D-J segment. This process was naturally made to be inaccurate because when two pieces of DNA are joined together, random bases can insert between them, forming ________________ of different sizes. If a junction is a multiple of _____ then it is a successful rearrangement which gives us a protein. If it is unsuccessful, then we cannot make a heavy chain protein. If it is successful, a ____-______ ____________________ is formed. This receptor is made to identify cells which have made good rearrangements and allow them to expand. This expansion requires signaling from ________________ __________________ __________________. This means that the pre-B receptor serves as a _____________________.
D and J
pro-B lymphocyte

V

junctions

3

pre-B receptor

Bruton's Tyrosine Kinase (BTK)

checkpoint
___________ is an X-linked gene and a relatively common immunodeficiency. If this is not functional, we cannot produce B cells. This is called ___-______________ __________________________.
BTK

X-linked agammaglobulinemia (XLA)
Normally, a stem cell develops into a _________________ ________________ __________________ which can further develop into B cells, T cells or Natural Killer cells. ________ will bind to the _______ ________________ on lymphoid progenitor cells to signal differentiation of T cells. In certain immunodeficient diseases, the genetic code of this receptor is defective which prevents IL-7 from binding to it and thus ruins the ability for progenitor cells to differentiate into T cells
lymphoid progenitor cell

IL-7
IL-7 receptor
Which primary immunodeficiency mainly impacts B cell development without affecting T cells?

1. X-linked agammaglobulinemia (XLA)
2. DiGeorge syndrome
3. RAG type SCID
4. X-linked SCID
1. X-linked agammaglobulinemia (XLA)
Individuals with X-linked agammaglobulinemia (XLA) are more susceptible to some kinds of pathogens than others. What pathogen do you think an XLA patient would be LEAST susceptible to?

1. Mycobacterium tuberculosis (an intracellular bacterium)
2. Streptococcus pneumoniae (an extracellular bacterium)
3. Staphylococcus aureus (an extracellular bacterium)
4. Giardia lamblia (an extracellular parasite)
1. Mycobacterium tuberculosis (an intracellular bacterium)

(reason: M. tuberculosis is the only intracellular pathogen listed. XLA is a deficiency of antibodies, which function almost exclusively outside of cells)
The number of B lymphocytes and T lymphocytes in the blood is an important component of the clinical diagnosis of primary immunodeficiencies. Which disorder would be most likely to lead to low blood counts of T cells and B cells?

1. X-linked agammaglobulinemia (XLA)
2. DiGeorge syndrome
3. RAG type SCID
4. X-linked SCID
3. RAG type SCID

(reason: RAG type SCID is caused by deficiency in genes required for VDJ recombination. Antigen receptor expression is required for B and T cell development and proper antigen receptors are not expressed without VDJ recombination. As a result, individuals with RAG type SCID have very low B and T cell counts)
The diversity of immune receptors of T and B cells is generated by __________ _________________________
VDJ recombination
____% of our B cells are self reactive75%__________________ __________________ (aka _____________ ________________) is the process of testing our T cells in the thymus to see which ones are self-reactive. The ones identified as self-reactive are given a signal to dieClonal deletion negative selectionIn the thymus, we have _________________ _______________ which attempts to suppress the expansion of self-reactive cells. If these cells creep out into the lymph nodes (the periphery), then we have a process called _______________ _________________ which will suppress the self-reactive cells that escaped the thymuscentral tolerance peripheral toleranceA ____________ _____ _______________ is what is used to suppress effector cells so they cannot damage our own cells. These cells mediate peripheral toleranceregulatory T cell___________________ ______________ is the process of allowing B cells, in the bone marrow (so its central tolerance), to undergo another round of gene rearrangement to produce a different light chain, making them no longer self-reactiveReceptor editingWhich of these factors does NOT contribute to the generation of self-reactive T cells? 1. nucleotides inserted between recombined gene segments 2. different combinations of α and β T cell receptor chains 3. millions of different inherited T cell receptor genes 4. genetic recombination3. millions of different inherited T cell receptor genesWhich of the following is a mechanism of peripheral tolerance that controls self-reactive effector B cells AND self-reactive effector T cells? 1. regulatory T cell suppression 2. clonal expansion 3. receptor editing 4. clonal selection1. regulatory T cell suppressionWhat is the main difference between central tolerance in the thymus and in the bone marrow? 1. Clonal deletion of B cells occurs in the thymus, while receptor editing of T cells occurs in the bone marrow. 2. Clonal deletion of T cells occurs in the thymus, while receptor editing of B cells occurs in the bone marrow. 3. Clonal deletion of B cells occurs in the bone marrow, while receptor editing of T cells occurs in the thymus. 4. Clonal deletion of T cells occurs in the bone marrow, while receptor editing of B cells occurs in the thymus.2. Clonal deletion of T cells occurs in the thymus, while receptor editing of B cells occurs in the bone marrow.Autoimmune diseases can be divided into two groups: one set of disorders are caused by defects of ________________ and another is caused by ____ ________________antibodies T cells__________________ ________________ causes a drooping eyelid because of a signal to the muscles of the eyelid that is inhibited. An auto-antibody is made that blocks the acetylcholine receptor so AcH cannot bind to the receptor and neuromuscular transmission cannot occurMyasthenia gravis___________ can cause kidney disease. Auto-antibodies bind to normal DNA which forms immune complexes. These complexes are made up of ______________, ______________ and ________________ proteins. These complexes have a particular shape and size and they deposit in the blood vessels. In the kidney, these cause __________________ _________________ (inflammation of the glomerulus)Lupus antigen antibody complement glomerular nephritis_______________ ____ ________________ is a T cell disorder where the pancreas becomes inflamed and insulin production is reduced. Immune cells infiltrate the pancreas and cause inflammation, damaging beta islet cells, losing endocrine function of the pancreas.Type I diabetes___________________ is a T cell disorder where T cells, specifically _______________, enter the skin and secrete cytokines, ______________. This cytokine recruits neutrophils which causes inflammationPsoriasis Th17 IL-17How do antibodies contribute to glomerulonephritis in lupus? 1. Antibodies opsonize key proteins involved in kidney function, triggering phagocytosis of kidney cells. 2. Antibodies form immune complexes, which cause inflammation that damages kidney vessels. 3. Antibodies neutralize a key molecule involved in kidney function. 4. Antibodies activate ADCC, which kills kidney cells.2. Antibodies form immune complexes, which cause inflammation that damages kidney vessels.How do antibodies contribute to myasthenia gravis? 1. Antibodies opsonize key proteins involved in nerve function, triggering phagocytosis of neurons. 2. Antibodies form immune complexes, which inhibit neuron function. 3. Antibodies neutralize a key molecule involved in neuron function. 4. Antibodies activate ADCC, which kills neurons.3. Antibodies neutralize a key molecule involved in neuron function.Monozygotic (identical) twins are approximately 50% concordant for type 1 diabetes (T1D). This means that if one twin has T1D, there is about a 50% chance that the other twin will also have the disease. T1D is not a common disease. This suggests that ____________. 1. T1D risk is determined entirely by genetic factors and environmental factors are not involved. 2. T1D risk is determined partially by genetic factors and partially by environmental factors. 3. T1D risk is determined entirely by environmental factors and genetic factors are not involved.2. T1D risk is determined partially by genetic factors and partially by environmental factors._____________________ are the most common immune disease. They involve IgE, _____________ _______________ and ___________________. The respond to common environmental antigens called _________________Allergies mast cells eosinophils allergens_______________________ is the first exposure to an allergen. The initiation of the response occurs in _________________ ________________ ____________, like the lymph node.Sensitization secondary lymphoid organIn the allergen B cell component, a helper T cell instructs B cells to change antibody isotype from IgM to ________. In this T dependent antibody response, there is a generation of plasma cells and memory B cells that produce this antibody. This antibody minds to surface receptors on _____________ __________. This makes this cell "_______________".IgE mast cells sensitizedIn the allergen T cell component, ______ cells are produced and differentiated from naive T cells. This type of T cell makes cytokines ___________ and __________. The latter causes growth and activation of eosinophilsTh2 IL-4 IL-5An allergen binds to IgE which causes movement of Fc receptors on the mast cell membrane. This movement of receptors towards each other is called ______________ _____________. This generates signals in the mast cell which cause it to release _______________, which contain a variety of amines that are active on blood vessels (i.e. histamine), ________________ _________________ ________________ (i.e. prostaglandins and leukotrienes), _____________________________ cytokines (i.e. TNF). The eosinophils release its granules which contain a set of _________________ that can be destructive to tissuecross linking granules lipid inflammatory mediators pro-inflammatory proteasesIf an allergen breaches the epithelial barrier in the airway, the ______ attached to a mast cell will bind the allergen, causing ___________ _____________ and activation of the mast cell which causes the release of the ________________ _________________ (i.e. histamine, TNF). These mediators will bind to the endothelial wall. This __(increases/decreases)__ leakiness of blood vessels so that fluid leaks out and causes swelling of the tissue. Because of TNF, the endothelial wall becomes sticky and promotes the migration of ________________ and other leukocytes out of the blood vessel and into the tissue (this is acute inflammation). This response to an allergen binding to IgE on mast cells is called the _____________________ ___________________ ________________IgE cross linking inflammatory mediators. increases neutrophils immediate hypersensitivity reactionIf an allergic reaction occurs in the skin, it can manifest as _____________. If it is inhaled, it can manifest as __________________ or __________________. If it is consumed, it can manifest as ________________ _________________, like diarrhea, abdominal pain and nausea and vomiting. If you suffer from a sting or injected drug, then mast cells can be activated all over the body causing a severe loss of blood volume due to leakage of many vessels. Also, there can be edema in the airways and bronchoconstriction. This systemic reaction is called ________________hives congestion asthma gastrointestinal symptoms anaphylaxisWhat distinguishes allergy from autoimmunity? 1. Allergy is a response to self antigens; autoimmunity is a response to environmental antigens. 2. Allergy is a response to environmental antigens; autoimmunity is a response to self antigens. 3. Unlike autoimmunity, allergy is treatable with immunosuppressants. 4. Unlike autoimmunity, allergy is mediated by T cells.2. Allergy is a response to environmental antigens; autoimmunity is a response to self antigens.Some "type 2" T follicular helper cells secrete IL-4 and IL-13. In response, B cells initiate class switching that favors the ___________ isotype, which plays a particularly important role in allergy. 1. IgA 2. IgE 3. IgG 4. IgM2. IgEIn addition to the cytokine IL-4, what signal do helper T cells provide to B cells that would favor B cell receptor affinity maturation and isotype switching? 1. CD40L 2. TNF-α 3. CD28 4. IL-21. CD40LA monoclonal antibody that binds to IgE is used as a drug to treat allergies. This anti-IgE drug directly interferes with a process that leads to activation of ____________. 1. macrophages 2. neutrophils 3. mast cells 4. Th2 cells3. mast cellsThe therapeutic antibody that targets IgE probably binds to what portion of the IgE antibodies that contribute to allergies? 1. light chain 2. variable 3. Fab 4. Fc4. FcWhich primary immunodeficiency would be most effectively treated by transfusions of IgG extracted from the blood of healthy adults? 1. DiGeorge syndrome 2. RAG type SCID 3. X-linked SCID 4. XLA4. XLAPlasmapheresis is a procedure that involves removing blood from a patient, fractionating it and discarding some fraction, then returning the blood to the patient. For example, this can be done to remove immunoglobulins from the blood but return leukocytes and red blood cells. Which of the autoimmune or inflammatory diseases below might be most effectively treated with plasmapheresis to remove immunoglobulins? (Select two answers.) 1. myasthenia gravis 2. type 1 diabetes 3. sarcoidosis 4. psoriasis 5. lupus1. myasthenia gravis 5. lupusHuman immunodeficiency virus (HIV) is a virus that primarily infects CD4+ T cells. As HIV infection progresses, CD4+ T cell counts drop precipitously. To which of the following diseases would a patient with HIV have increased susceptibility? (Select all that apply.) 1. Mycobacterium tuberculosis (an intracellular bacterium) 2. Streptococcus pneumoniae (an extracellular bacterium) 3. Pneumocystis jirovecii (a fungus) 4. Herpes simplex viruses1. Mycobacterium tuberculosis (an intracellular bacterium) 2. Streptococcus pneumoniae (an extracellular bacterium) 3. Pneumocystis jirovecii (a fungus) 4. Herpes simplex virusesWhat immune mediator, below, is most typically associated with allergy? 1. IL-4 2. IFN-β 3. IL-10 4. IL-171. IL-4All of the genetic defects described below exist at very low frequency in the human population. Which loss-of-function mutation would be most likely to lead to autoimmune disease? Assume each mutation causes a complete loss of function of the associated gene. 1. Disruption of the RFX5 gene which is necessary for proper MHC class II expression. 2. Disruption of the RAG1 gene which is necessary for V(D)J recombination. 3. Disruption of the FOXP3 gene which is necessary for Treg development. 4. Disruption of the IL-17RA gene which encodes the IL-17 receptor.3. Disruption of the FOXP3 gene which is necessary for Treg development.Anaphylaxis is an acute allergic response. What aspects of allergic anaphylaxis are the most immediately life-threatening? (Select two answers.) 1. low blood pressure 2. airway constriction 3. diarrhea 4. hives 5. itch1. low blood pressure 2. airway constrictionIn this lesson, we discussed mechanisms of central and peripheral tolerance for T cells. Imagine a self-reactive T cell that has not undergone clonal deletion in the thymus (that is to say, it has escaped central tolerance). If it encounters self antigen in the absence of an infection or inflammation, what will happen to this self-reactive T cell? (Select two answers.) 1. The T cell undergoes clonal expansion. 2. The T cell gains effector functions. 3. The T cell undergoes apoptosis. 4. The T cell becomes activated. 5. The T cell becomes anergic.3. The T cell undergoes apoptosis. 5. The T cell becomes anergic.