Perturbations in the Super System Flashcards
What are superantigens?
In contrast to conventional peptides that require uptake and processing prior to presentation by T-lymphocytes, superantigens interact with the “side” of the MHC Class II-TCR complex
-Effectively, they cross-link MHC Class II to T-cell receptors
Give two examples of superantigens
Toxic Shock Syndrome Toxin-1 (TSST-1) and Staphylococcal enterotoxin (SE)
What follows in response to superantigen binding?
Cytokine storm: polyclonal extensive activation of T cells leads to the over-production of TNFalpha (and IL-1/6)
Which are the 4 hallmark signs of toxic shock syndrome?
Fever, hypotension, rash, desquamation (1-2 weeks after illness, particularly involving the palms and soles of your feet)
Toxic Shock Syndrome is caused by toxin released from what bacteria?
Staph Aureus
The clinical manifestations of TSS are precipitated by what immune response?
Cytokine storm —> disease
Causes low blood pressure, fever, diarrhea, shedding of skin
CCR5 deficient individuals are resistant to what virus, but very susceptible to what other virus?
Resistant to HIV
Susceptible to West Nile Virus
What is CCR5?
CCR5 is a chemokine receptor for chemokines that attract and direct the migration of T cells to the site of infection
CCR5 is located ON the T cells
Why are CCR5 deficient individuals resistant to HIV?
CCR5 is a co-receptor (along with CD4) for binding and entry into human T-lymphocytes by HIV-1
Why are CCR5 deficient individuals susceptible to west nile virus?
They are susceptible because T-cells cannot taxi to the site of infection, as they cannot follow the CCR5 signal
What is the most cytokine produced by virally infected cells?
Interferons.
Interferons then activate macrophages, dendritic cells, they drive a Th1 response (CD8+, B cells) and NK cells
In contrast to most viruses, certain viruses have the capability of directly inducing IL-10 (such as HIV). What is the consequence of this?
IL-10 is very immunosuppressive.
This reduces the capacity of DCs and macrophages to wage war, drives a Th2 response, and reduces the immune response in general
How does the herpes virus suppress the immune response?
The herpes virus has acquired human IL-10 in their genome, so when they infect a cell and start to replicate, they produce immunosuppressive IL-10
List 4 ways viruses can alter chemokine function to benefit their survival
1) Chemokine secretion attracts susceptible cells for further infection
2) Chemokine secretion attracts infected cells to distant tissues
3) Chemokine receptor function or expression may be inhibited
4) Chemokines and/or receptors may be sequestered inside the cell
Autoimmune diseases are caused by self-reactive what?
T and B lymphocytes
How do genetics play a role in autoimmune diseases?
Some people are genetically predisposed to autoimmune dysfunction
Females are disproportionately affected by autoimmune diseases (3:1) (after puberty- sex hormones contribute)
Also, females have a more vigorous Th1 response to antigen and more successfully produce antibodies
Peripheral tolerance is enforced by which cells?
CD4+25+ FoxP3+ T regs
During what recombinant process can self-reactive B cells be generated? How are they usually controlled?
Somatic hypermutation.
They usually die from neglect or are downregulated by Tregs
Goodpasture’s syndrome is an organ specific autoimmune disease against which organ?
Lung and kidneys
Myasthenia gravis is an organ specific autoimmune disease against which organ?
neuromuscular
MS is an organ specific autoimmune disease against which organ?
The brain
Lupus is a systemic autoimmune disease against what?
Basement membranes
Autoimmune cells of Insulin dependent diabetes mellitus type I are primarily of what type?
CD8+ , with some antibody response, against pancreatic beta cells
What is Grave’s disease?
Ab against TSH receptor activates the receptor and leads to excessive thyroid hormone/hyperthyroidism
What is Goodpasture’s syndrome?
Ab to type IV collagen –> pulmonary hemorrhage and glomerulonephritis
What is Myasthenia gravis?
Ab to acetylcholine receptor. Blocks neurotransmission –> muscle weakness
What is multiple sclerosis?
CD4+ cells react with the myelin sheath –> demyelination
What is lupus?
Ab to DNA –> immune complex deposition at basement membranes
What is Rheumatoid arthritis?
CD4+ response that stimulates an inflammatory response within the joints
Define Type II hypersensitivites
Ab against cell-surface or extracellular matrix antigens
Define Type III hypersensitivites
Ab-antigen immune complex deposition
Define Type IV hypersensitivity
delayed type- T-cell mediated
Name three type II hypersensitivity autoimmune diseases
Graves, Myasthenia Gravis and Goodpastures
Name a type III hypersensitivity autoimmune disease
lupus
Name three type IV hypersensitivity autoimmune diseases
Insulin Dependent Diabetes Mellitus type I, Rheumatoid arthritis and Multiple sclerosis
How are C3 levels affected by lupus?
C3 levels are low. All of the immune-complexes formed attract C3 deposition and C3 cannot be replenished fast enough
Pancreatic beta cells are almost selectively damaged by what viruses?
Mumps, rubella, and coxsackie B
What is Rheumatoid factor?
IgM, IgG and IgA specific for IgG. This leads to immune complex formation and increases inflammation
What portion of people with rheumatoid arthritis have rheumatoid factor?
85%
Describe the basic sequence of events that leads to inflammation of joints in people with rheumatoid arthritis
Unknown trigger begins inflammation in synovial joints
Autoreactive T cells activate macrophages
MACROPHAGES SECRETE IL-6 AND TNFalpha that interacts with the fibroblasts
Fibroblasts release MMPs that destroy tissue, along with RANK-ligand (which activates osteoclasts to break down bone)
What is the autoantigen in multiple sclerosis?
Basic myelin protein
How do T-cells get across the blood brain barrieR?
They sneak in when the brain is inflamed
Inflammation makes the brain locally permeable to leukocytes and blood proteins
What activates autoreactive T cells in the brain in MS?
Microglial cells present antigen to autoreactive T cells
This sets up an inflammatory reaction
Name four risk factors for autoimmune diseases
1) Genetics (mostly HLA-DR)
2) Female
3) Environmental (smoking with RA)
4) Infections
