Name 4 ways that the immune system can dysfunction.
1) Pathologic conditions caused by normal immune response
2) Conditions caused by defects in immune regulation
3) Autoimmune disease
4) Immunodeficiency
How many people are infected with Mycobacterium tuberculosis?What percentage of the population has a risk of developing TB?
1/3 of the world population
5-10%
When TB is active, how is the pathology created?
By normal immune system function
What happens when an individual inhales the TB organism from an infected individual?
The organism is engulfed by alveolar macrophages/dust cells into a phagosome which should fuse with a lysosome to destroy the organism, but this is where it can go wrong
In TB, when the organism is engulfed, what can go wrong?
The TB organism modifies the surface of the phagosome so it’s unable to fuse with the lysosome, so the organism can thrive and multiply in the macrophage. Eventually, it busts out of the macrophage, killing it and as it dies by necrosis, the contents of its lysosome are released into the lung tissue.
In TB, what happens when the contents of the lysosome are released into the lung tissue?
It initiates an inflammatory response which recruits other immune cells to the battle site. This causes more inflammation.
What are the results of the inflammatory battle site in the lung tissue in a person with TB?
1) The person dies
2) The person recovers
3) The person lives with chronic infection
How can a person recover from a TB organism causing a battle site in the lung tissue?
1) The battle causes release of cytokines like INF-y that hyperactivates macrophages.
2) Macrophages and other cells (neutrophils) eliminate the invader
3) Adaptive immune system response also comes into play (T cells)
4) Vitamin D simulates the release of cathelicidins
When does sepsis occur?
Sepsis occurs when chemical released into the bloodstream to fight the infection trigger inflammation throughout the body which can trigger a cascade of events that can damage multiple organ systems, causing them to fail
What happens when sepsis progresses to septic shock?
Blood pressure drops dramatically which may lead to death
What population is sepsis most common in?
Elderly people or those with weakened immune systems
How many people die per year in the US due to sepsis?
250,000
Is gene mutation that has never been observed in human lethal?
Yes! (I have this written that it will be on the exam in my notes)
What cytokine is involved in sepsis?
TNF
How is TNF involved in sepsis?
TNF that is secreted by macrophages systemwide can increase vascular permeability causing large amounts of fluid loss, decreased blood volume and decreased blood pressure causing septic shock and heart failure
How are positive feedback loops of the innate immune system linked with sepsis?
Sepsis and shock can result when positive feedback loops cause an overreaction to a system wide infection
What nerve can decrease macrophage release of TNF?
Vagus
What percentage of the US suffers from type I hypersensitivity reactions which include most common allergies?
54%
Is allergy associated with Th2 or Th1 bias?
Th2
What causes allergies?
The overproduction of IgE antibodies in response to otherwise innocuous environmental antigens that causes allergies
What immunoglobulin is overproduced in allergies?
IgE
Are non allergic reaction Th1 or Th2 bias?
Th1
What immunoglobulin is associated with non- allergic reactions?
IgG Ab
In allergies, the Fc end of the IgE binds to what cells?
Mast cells
In allergies, the Fab end of IgE binds to the allergen which triggers what?
It triggers the mast cell to degranulate
What happens on subsequent exposures to an allergen?
The allergen can cross link IgE.. This clustering sends a signal downstream promoting degranulation of mast cells releasing histamine, proteases, heparin, and other chemicals causing familiar symptoms
What are the two phases of allergies?
1) Immediate
2) Delayed
What happens in the immediate phase of allergies?
Associated with degranulation of mast cells which are stationed out in the tissues and degranulation of basophils are recruited from the blood by signals given off by mast cells.
What causes the degranulation in the immediate phase of allergies?
Both bind IgE and resulting cross linking of Fc receptors
In the immediate phase of an allergic reaction, what do the Th cells secrete?
They secrete cytokines like IL-5 which can recruit many eosinophils from bone marrow
What happens in the delayed (chronic) phase of allergies?
Eosinophils play a prominent role and add to the response but their effect is delayed because the majority of them must be recruited from the bone marrow (this takes time)
What is the normal function of mast cells, basophils, and eosinophils?
Geared to provide a defense against parasitic infections that are too large to be phagocytized by macrophages and neutrophils
What immunoglobulin acts as a guidance system for mast cells, basophils, and eosinophils?
IgE by targeting their chemistry at the parasite to destroy it
Can mast cells, basophils, and eosinophils degranulate to any other immunoglobulin?
No, they should only be able to degranulate in response to IgE binding to parasite, limiting collateral damage
Is a fetus supposed to be more of a Th1 bias or Th2 bias? Why?
Its more of an advantage for the fetus to have a Th2 bias because the 1/2 of the genetic material is paternal and could be considered foreign by the mother
What cytokines are involved in a Th1 bias?
TNF which helps activate NK cells and IL-2 which causes proliferation of NK cells and CTLs
What is the role of the placenta in Th2 bias?
The placenta produces large quantities of IL-4 which causes both maternal and fetal helper T cell to become Th2
What is thought to shift newborn’s back to Th1 bias after birth?
Contact with microbes, especially those found in soil
Besides contact with microbes what other things may prevent allergies or asthma from forming?
1) Early childhood infections
2) Children who grow up on farms
3) Children with older siblings
4) Children who grow up with dogs
What is the percentage of allergy concordance in identical twins?
50%
What type of gene is inherited in people who are atopic?
Class II MHC genes- they code for MHC proteins that may be especially proficient at presenting antigen/allergies
What promotes class switching of B cells to produce IgE?
Mutant forms of IgE receptor that sent an unusually strong signal when cross linked resulting in high levels of IL-4
What are some common treatments for allergies?
1) Glucocorticoids (cortisol)- blocks cytokine production by Th cells activating fewer B cells
2) Xolair- block binding of IgE to mast cells
3) Claritin- histamine blocker
4) Chiropractic and other homeopathic alternatives
What is the down side to using glucocorticoids?
Increased susceptibility to infectious disease as you generally suppress immune system function
How does immunotherapy work to cure allergies?
Injections of gradually increasing doses of allergens until tolerant. Takes several years. If it works the B cells class switch from IgE to another antibody class like IgG.
What are allergen-specific Th cells polarized to?
A Th2 cytokine profile (IL-4, IL-5, and IL-13)
When does autoimmune disease result?
When a breakdown in the mechanisms meant to preserve tolerance of self is severe enough to cause a pathological condition.
What percent of people in the US do autoimmune diseases affect?
5-7.5%, more common in women than men
How can infections lead to autoimmune disease?
Lymphocytes have receptors that recognize their cognate antigen on the microbe. The receptor may cross react with a self antigen causing an autoimmune disease (MOLECULAR MIMICRY)
What happens when self reactive T cells that are activated by microbial mimics reach the tissues?
They might cross react with self antigens and must be continually re-stimulated
What happens to the self reactive T cells if they are not continually re-stimulated in the tissues?
They die by apoptosis
What happens to the self reactive T cells if they encounter self antigens that do not provide adequate co-stimulation?
They are anergized or deleted
Does the innate immune system or the adaptive immune system function during autoimmune diseases?
The innate system gives the adaptive immune system permission to function
What cells are activated during autoimmune diseases?
The APC’s are activated by inflammatory cytokines (TNF and IFN-y) from innate immune cells. Once activated the APCs express MHC and co-stimulatory molecules required to re-stimulate T cells in that tissue
What has to happen before T cells can be re-stimulated?
Inflammation, otherwise the T cell would never get the co-stimulation necessary to activate
Sill in autoimmune diseases… What can cytokines up-regulate on normal cells in the tissue?
MHC I, which makes these cells better targets for destruction by self reactive CTL’s
What reflexes control inflammation?
Neural reflexes (vagus)
What is insulin dependent diabetes mellitus?
Autoimmune destruction of pancreatic beta cells mediated by CTLs possibly with help from Ab from self reactive B cells (insidious onset)
What is Myasthenia gravis?
Self reactive antibodies against the Ach receptor presents Ach from binding producing muscle weakness and autonomic dysfunction
What is multiple sclerosis?
Immune system attack on myelin in CNS. Thought to be due to self-reactive T cells
What is rheumatoid arthritis?
T cell attach on cartilage protein in joints. IgM and IgG antibody complexes can activate macrophages leading to chronic inflammation
What is lupus erythematosis?
Long-term autoimmune disease that may affect skin, joints, kidneys, brain and other organs leading to chronic inflammation. Breakdown in B and T cell tolerance
What is Guillain-barre?
Immune system attack on myeline in PNS
What is transverse myelitis?
An inflammatory process of the spinal cord, and can cause axon demyelination
What is autoimmune lymphoproliferative syndrome?
Genetic defect where T cells refuse to die when chronically stimulated by self antigens
What are the conditions for autoimmune disease?
1) Person must have MHC molecules that can present self antigen
2) Person must have T lymphocytes and sometimes B lymphocytes with receptors that can recognize the self antigen
3) Must be environmental factors that lead to the breakdown of the tolerance mechanisms which are designed to eliminate self reactive lymphocytes
What do autoimmune diseases typically follow?
Bacterial or viral infections, microbial attack, and chronic inflammation
What is the hypothesis as to why infections may lead to breakdown of self tolerance leading to immune disease?
Molecular Mimicry
What cells recognize the cognate antigen?
BCR and TCR
Is it enough for a microbe to activate self reactive T cells by mimicry?
No, there must also be an inflammatory reaction going on in the same tissues that express self antigen, otherwise it is unlikely that the self reactive lymphocytes would exit the blood into the tissues
What is the result of inflammation?
APCs are activated that can re-stimulate self reactive T cells
How can inflammation be down regulated?
By the vagus!! “the inflammatory reflex” which is a cholinergic anti-inflammatory pathway
What are 2 causes of immunodeficiency?
Genetic defects and AIDS
What cells aren’t functioning properly in single gene mutations?
Non functional CD40 (B cell) or CD40L (Th cell)
What organ do the single gene mutations affect?
Affect the formation and function of the thymus like in DiGeorge Syndrome
What cells aren’t functioning properly in severe immunodeficiency syndrome (SCIDS)?
Neither B cells not T cells function
What do you think about a genetic mutation that has never been observed in human? (**he said this would be a question!!)
It’s lethal!
What is the incidence of AIDS?
About 34 million people worldwide
How does AIDS knock out immune function?
By targeting Th cells
When do people usually die of AIDS?
They usually die due to opportunistic infections like Pneumocytis carnii and Kaposi sarcoma
What happens to Th cells during the chronic phase of HIV?
The total number of Th cells gradually decreases eventually crippling the immune system
How can HIV-1 defeat the immune system?
1) It is a slowly replicating lentivirus
2) Uses a viral enzyme to make a copy DNA that can be inserted into host DNA and here it can sit in a latent state which cannot be detected by CTLs
3) High mutation rate allows virus to evade immune system
What cells are infected by HIV-1?
Helper T cells, macrophages, dendritic cells, docks to CD4 protein via GP120 on virus
What is the treatment for HIV-1?
HAART
What do innate immune cells secrete more of when infected with HIV-1?
IFN- alpha and IFN-beta