Module 47 Flashcards
1
Q
Compare the innate and adaptive immune systems
A
- The adaptive immune system is what most people think of when they think of the immune system.
○ It is composed of T cells and B cells, and the B cells mature to plasma cells that can make antibodies when activated.
○ T cells, both helper T cells and cytotoxic T cells have receptors that recognize and respond to processed antigens, either presented by antigen presenting cells in the case of helper T cells, or on the surface of other cells in the case of cytotoxic T cells. These cells can produce a specific response to almost any antigen because T cell receptors and antibodies are produced from genes that undergo random rearrangement to produce an almost limitless diversity.
○ The adaptive immune response is HLA (human leukocyte antigen) restricted, which means that the T cells and B cells must be stimulated by antigen presenting cells from the same individual.
○ There are memory T cells that produce a faster response on rechallenge with an antigen. The adaptive immune system developed in vertebrates, and is not present in more primitive species.- In contrast, the effector cells of the innate immune response are macrophages, neutrophils, NK cells, and gd-T cells.
They can only respond to pathogen-associated molecules such as lipopolysaccharide that are coded for in their DNA and are detected by molecules such as toll-like receptors. They also appear to be able to respond to cell stress. There is no memory.
- In contrast, the effector cells of the innate immune response are macrophages, neutrophils, NK cells, and gd-T cells.
2
Q
Although it is more complicated, what is the common name for T cells that express CD4 and CD8, respectively?
A
CD4 T cells are commonly referred to as helper T cells, and CD8 T cells are usually cytotoxic T cells.
3
Q
What serious viral infection provides evidence for the importance of CD4 T cells in an immune response?
A
HIV infections target CD4 T cells, and the CD4 T cell count is a good measure of how impaired a patients immune system is likely to be
4
Q
Describe the process of activation of CD4 T cells by antigen presenting cells. What are signal 1 and signal 2?
A
- Antigen presenting cells present antigens in the groove of MHC-II to the T cell receptor of CD4 T cells. This represents signal 1.
- In order to produce an immune response the antigen presenting cells have to be activated.
- When the antigen presenting cells are activated there is an increase in the expression of co-stimulatory molecules on the antigen presenting cells such as B7 (otherwise known as CD80 and CD86) and CD40.
- B7 interacts with CD28 on T cells, and CD40 interacts with CD40L on T cells. These costimulatory signals represent signal 2.
Both signal 1 and signal 2 are required for activation of the CD4 T cells. If CD4 T cells receive signal 1 without signal 2 the result is immune tolerance or anergy.
5
Q
To what does CD4 bind? How about CD8?
A
- CD4 binds to MHC-II (major histocompatibility complex, which is HLA in humans) and CD8 binds to MHC-I.
- All nucleated cells express MHC-I (red cells and platelets don’t), but only antigen presenting cells express MHC-II. However, MHC-II can be expressed by other cells during inflammatory responses.
6
Q
What is different about the form of the same antigen that is recognized by a T cell and a B cell?
A
- T cells recognize small peptides that come from processing larger molecules and are presented in the context of MHC-I or MHC-II.
- B cells recognize the complete molecule, usually a protein.
7
Q
What type of antigen usually produces an antibody response, and what type usually produces a cell-mediated response?
A
- Soluble antigens are taken up by antigen presenting cells and presented in the context of MHC-II to CD4 helper cells and are more likely to induce an antibody response.
- In contrast, intracellular antigens such as viruses are presented in the context of MHC-I and are presented to CD8 T cells; therefore, they more likely to induce a cell mediated immune response.
- However, although the dominant response may fit this pattern, immune responses are usually mixed.
8
Q
Describe the steps involved in the initiation of an immune response to an antigen that penetrates the skin. Include in the description where these steps occur.
A
- The antigen must cause some type of inflammation that activates skin antigen presenting cells such as Langerhans cells.
- These cells are continuously taking up antigens, but when activated they stop taking up new antigens and travel to the draining lymph node where they are more likely to encounter T cells and B cells that recognize the antigen presented by the antigen presenting cells.
- The activated lymphocytes enter the blood stream and are attracted to the site of inflammation by chemokines.
9
Q
What is an adjuvant? Is squalene dangerous?
A
- Adjuvants are agents that activate antigen presenting cells.
○ As indicated above there is no immune response unless the antigen presenting cells are activated.- Janeway referred to adjuvants as the “immunologist’s dirty little secret” because antigens are ignored unless they cause some type of inflammation. That is why vaccinations always contain some type of adjuvant.
- The activation occurs through PAMPS (pathogen associated molecular pattern molecules) or DAMPS (danger associated molecular pattern molecules).
Squalene is an endogenous molecule, which is the precursor to cholesterol. However, antigens presented in oil lead to activation of antigen presenting cells, so in this formulation the “natural” squalene acts as an adjuvant. Squalene is not a dangerous molecule as some antivax advocates would claim
10
Q
Do vaccinations cause autism?
A
Definitely not! First it was claimed that thiomersal, a mercury compound used as a preservative in some vaccines, was the cause.
- The amount of mercury in a dose is very small (Somewhere I read that if you eat a tuna fish sandwich and receive an immunization containing thiomersal, the concentration of mercury where the vaccine was injected will be lower than in the rest of the body. However, I have not been able to confirm this.) - It was predicted that when the thiomersal was removed the incidence of autism would plummet. Thiomersal was removed from childhood vaccines in Canada some 20 years ago and a little later in the US, but of course the incidence of autism did not decrease. - Several very good studies have been done that show that there is no association between childhood vaccinations and autism. What is true is that autism often becomes evident about the time of many vaccinations, and it was not unreasonable to suspect that there might be an association.
11
Q
Do probiotics such as yogurt make you healthier.
A
- I am skeptical. There is a large and growing amount of data to indicate the importance of the microbiome. However, the gut microbiome is very complex and composed mostly of anaerobic bacteria.
- Giving a simple probiotic such as yogurt, which contains aerobic bacteria is unlikely to have an important effect for most conditions. I thought there might be some benefit for things such as urinary tract infections, but a recent Cochrane review found no evidence of benefit.
More concentrated anaerobic bacteria may be more effective but may cause other problems.
- Giving a simple probiotic such as yogurt, which contains aerobic bacteria is unlikely to have an important effect for most conditions. I thought there might be some benefit for things such as urinary tract infections, but a recent Cochrane review found no evidence of benefit.
12
Q
Are there conditions that probiotics are effective at treating and are there any adverse effects of probiotics?
A
- There are conditions for which specific probiotics appear to be useful such as antibiotic associated diarrhea, but probiotics can also have adverse effects.
○ For example, the small intestine is normally sterile, and if a person takes a large number of bacteria it can cause small intestinal bacterial overgrowth. This is more likely to occur if the patient is taking a proton pump inhibitor.- In one study they found that the bacteria could produce D-lactic acid (The common lactic acid is L-lactic acid) and this produced CNS symptoms such as confusion. This is unlikely to occur with products such as yogurt, which contain much smaller numbers of bacteria. I
- it appears that some probiotics can even prolong the length of time that it takes for normal bacterial flora to be reestablished after antibiotic treatment. Therefore, it is important to use probiotics that have been shown to be effective for specific conditions.
13
Q
What are some new drugs that target the immune system?
A
It is clear that most chronic diseases, even things such as cardiovascular disease, have an immune component. The hottest new area of cancer treatment also involves manipulation of the immune system. Many of the new drugs are antibodies and other biologics. This is probably the fastest growing segment of the pharmaceutical industry
14
Q
Name several diseases that are likely to be mediated by the immune system.
A
- multiple sclerosis, type I diabetes, inflammatory bowel disease, arthritis, lupus, and even cardiovascular disease and dementia probably have an immune component.
- There are many other less common diseases such as thyroid disease, Addison’s disease, autoimmune hepatitis, etc, etc.
Most chronic diseases are either immune mediated or have a significant immune component.
- There are many other less common diseases such as thyroid disease, Addison’s disease, autoimmune hepatitis, etc, etc.
15
Q
Compare the structure, mechanism of action, ADME, and toxicity of cyclosporin and tacrolimus.
A
- These immunosuppressants revolutionized organ transplantation, and they are also used for a variety of other diseases. They are large molecules and yet can be given orally.
- They are substrates for P-glycoprotein, which limits their oral bioavailability to some degree.
- As would be predicted by their size, they are substrates for CYP3A4.
- Although the initial target is different, both cyclosporin and tacrolimus are calcineurin inhibitors that decrease IL-2 production.
○ IL-2 is essential for lymphocyte proliferation. - The limiting toxicity for both drugs is kidney damage.
○ they both can also cause diabetes, but the risk with tacrolimus is greater than that for cyclosporin.
Of course any immunosuppressant increases the risk of infection.
