Microbiology I Flashcards
Explain the possible mechanisms of induction of Autoimmunity For each autoimmune disease, recognize the symptoms, describe the autoimmune mechanism, list what type of hypersensitivity reaction is involved, and discuss potential treatments Discuss the experimental approaches to treatment of Autoimmune disease
Myasthia Gravis
Ach receptor affected , so ACh released from presynaptic neuron has nowhere to bind
Antibodies binding to cells/tissues
non-cytotoxic: wont kill the tissue initially
; only Change the FUNCTION of the tissue
-Altering its normal function
Who are most affected by Autoimmune diseases?
Females
What plays a major role in inducing autoimmunity?
Hormones
What is tightly controlled?
T cell activation
What is autoimmunity?
The response of the immune system against self components
- can be organ specific and systemic
What are the defining characteristics of autoimmunity?
autoantibody or auto reactive T cells specific for self antigens
What percentage of the human population is affected by autoimmunity?
5-7 %
What resembles immune effector mechanisms?
Hypersensitivity reactions II-IV
Mechanisms of autoimmunity
Breakdown of tolerance Release of sequestered antigens Molecular mimicry Inappropriate expression of HLA Polyclonal B cell activators Genetics AIRE
What is the breakdown of tolerance?
Deletion
Anergy
Suppression
The mechanism is compromise (trauma, infection)
HLA-B27
Ankolytic spondylitis
however, doesn’t necessary mean your will get it
Infection
leads to biological mimicry
Normal T-cell activation
MHCII + TCR
CD28 + B7 = activation molecules send the cell to an activated state - Don’t have co-stimulatory molecules
tightly controlled
Anergy
Lack of stimulatory signal
CTLA is in the place of CD28 => CTLA-A binds B7 = blocks activation signal
Soluble CTLA can deactivate signal
What does lack of CTLA-4 favor?
can spike increase in autoimmunity
Producing less sCTLA4 linked to autoimmune diseases
T cell maturation
Any T cell that was very reactive to MHC got deleted in the thymus
Mechanism of Tolerance
Thymic epithelium cells present T cells with a wide range of auto antigens
T cells which bind to antigen with high affinity in the thymus are deleted through negative selection
Antigens such as DNA are usually only represent inside cells and if they do escape, are cleared by complement or natural antibodies
Express co-stimulatory molecule
Barriers
Some tissues are protected from T cells by physical barriers** e.g. eyes and brain
(A lot of protective spaces where the immune system don’t have access to)
Trauma/inflammation can allow immune cell to pass through - which will mean that the immune system will not recognize environment vs self ?
Breakdown of Tolerance
Self antigen is missing from the thymus or MHC is unable to bind antigen
Few auto reactive T cells are deleted and more escape to the periphery
DNA may leak out of dying cells and is not cleared if complement is defective
Physical barriers round cells may become defective
If a tissue becomes infected cells of innate immune response express co-stimulatory molecules and secrete cytokines
Molecular mimicry
infection can trigger molecular mimicry
Pathogens express proteins with regions that are similar to self components
when will Intracellular type of antigens will not be sequestered?
high cell turnover
intracellular content release
immune response by random association -> immune complex deposition
Lost of T cell suppression
T regulatory cells suppress auto reactive CD4 T cells - requires direct contact e.g. IL-4, IL-10 produced = requires them to interact with CD4 T cell that is on the same APC as the Treg cell
What is FoxP3?
Treg cells typically have FoxP3
Loss of FoxP3 = less regulation = autoimmunity
a transcriptional repressor
found on X chr.
What kind of signal that CTLA-4 send?
inhibitory
suppresses CD4 T cells
Mutation of FoxP3 - a problem with the regulatory cell
Defect in suppressor protein
Observed in Chron’s disease and inflammatory bowel disease
Release of sequestered antigens
Tissue antigens not seen by developing T cells (sequestered) will not induce tolerance
Exposure of T cells to normally sequestered antigens at a later time may result in their activation
What mechanisms induce the release of sequestered antigens?
Trauma
Infectious agents
SLE = systemic lupus
T cells exposed to normally sequestered antigen = immune response will occur
Ab against intracellular proteins e.g. histone proteins (nucleosomes)?
Abnormally number of turnover and cells dying
Immune complexes circulate and go wherever they want ****
SLE patients also have increased IFN-y which mediates the ectopic expression of MHC by many different cells
What is one way pathogens escape?
Hijack and copy self peptides
-molecular mimicry
Agents that use molecular mimicry with Viral peptides and MBP (myelin basic protein)
Influenza Adenovirus Polio virus Epstein Barr virus Hepatitis B virus and associated DISEASES
What diseases associated with molecular mimicry
Post rabies encephalitis Polyoma Rheumatic fever Rous sarcoma Abelson leukemia -both from viral peptides
In many different cases, pathogens will have quite a few similarities with peptides . What is a classic example?
Cytomegalovirus has the similar stretch of peptides as HLA-DR
which causes immune response against Class II MHC
Ectopic expression of MHC
MHC Class II are on APCs e.g. macrophages, dendritic cells, B cells
Interferon gamma upregulates or increase MHC II in all different types of cells during extensive infection
These are targeted for the immune system
What are the diseases associated with ectopic expression of MHC?
IDDM - insulin-dependent diabetes mellitus
Grave’s disease
what are the different types of cells to which the IFN-yacts to increase or up regulate MHC?
pancreatic beta cells
intestinal epithelial cells
melanoma cells
thyroid acinar cells
What can trigger inflammatory response and increase IFN-y
Trauma (infection) in organ
Induced expression of MHC
Some cells do not normally express MHC II
Trauma (infection) trigger inflammatory response
What cells do not normally express MHC II ?
Thyroid epithelial cells in Grave’s disease
Pancreaetic beta cells in IDDM
What do T cells do in Grave’s disease?
Activated T cells recognize thyroid peptides presented by MHC class II and induce autoimmune thyroid disease
Polyclonal B cell activation without antigen binding
EBV enters B cells through non-tranditional route -> increase production of IgM in B cells?
Other agents that do this are gram negatives and CMV
-cause indiscriminate or non-specific activation (bypass all the specificities)
HLA association
Association of HLA aerotype with susceptibility to autoimmune disease
HLA Class II
Mostly indicated e.g. HLA DR3
What is the relative risk of just having DR2?
4.2
All the Ds are class II HLA
Ankylosing spondylitis
HLA aerotype B27
Relative risk 87.4 (more than other HLA association)
Sex ratio (male:female) : 0.3
more females affected
AIRE
Autoimmne regulator
transcriptional activor in the thymus
responsible for inducing the expression of 1200 genes for T cells so the T cells know what is self vs non self
It allows the T cells to see the self antigens and undergo negative selection
What happens when the AIRE is lacking?
antigens are not present in the thymus, which means that potential self reactive T cells are not removed
-causing autoimmunity in the peripheral organs
Autoimmune polyglandular syndrome
Lack of AIRE
affected individuals develop a wide rage of autoantibodies against endocrine glands, liver, skin, blood cells, and platelets
Thymus education
Occurs via extensive gene expression in other tissues
What HLA association links to MG?
HLA DR3
What are the Sx of MG?
progressive muscle weakness, droopy eyelids, double vision, eventually other face muscles weaken and similar effects can occur on the chest muscles which can impair breathing
How to differentiate between MG and MS
MS is spastic because you attack myelin
MG is weakness of muscles
What is the early Sx of MG and MS ?
Start with vision problems (double vision)
droopy eyes
paralysis
MG and inflammation
auto-ab specific for Ach rcpt -> activation of complement -> inflammation
How to diagnose MG?
Anti-Ach ab in the serum
How is MG tx?
anti-cholinestereases, immunosuppresion. plasmapheresis and thymus removal
Type III hypersensitivities
Rheumatoid arthritis
Systemic lupus erythematosis
Rheumatoid arthritis
cause chronic inflammation of the joints triggered by a immune complex ; can be hypersensitivity type IV Affects 1-3 % population Females affected 3x more 20-40 years HLA-DR4 association (rr=4.2)
Tx for Systemic Lupus Erythematosis
Glucocorticoids
Why is RH considered type IV?
Macrophages + Tcell recruitment = tissue destruction
Rheumatoid factor
IgM Ab binding specific for Fc of IgG
What cells infiltrate the joints in Rheumatoid arthritis ?
chronic inflammation:
Leukocytes including CD4, CD8, B cells, plasma cells, neutrophils and macrophages infiltrate into the joint synovium
Diagnostic for Rheumatoid arthritis
Rheumatoid factor but not always present
Thus, use elevated IgG and IgM
Tx for Rheumatoid arthritis
NSAIDs (COX-2 inhibitors), corticosterioids, immunosuppresion, gold therapy, anti-TNF-a (infliximab)
Presentation for SLE
Females 15x affected
20-40 years of age
African American ad Asian women
HLA-DR3 (rr=5.8)
What kind of inflammatory disease is SLE?
chronic
-involves almost every organ system, Sx depend on organ effected
SLE is a multi-system disease. What antigens are targeted
Auto-ab to almost every tissue antigen including histones, DNA, RNA, clotting factors
Disease effects dependent on area of complex deposition
Mechanism of SLE
Immune complexes form and deposit in various tissues
Complement binds
inflammation
necrosis - lumpy bumpy pattern of immune complexes
Diagnostic for SLE
Anti-DS DNA is specific test
Tx of SLE
NSAIDs, corticosteriods, immunosuppression, anti-malarial drugs
Pathogenesis of SLE
Type III HS - lumpy bumpy pattern of deposition
spotty and throughout the kidney
Cause nephritis
Sx : butterfly formation rash on the face
Type II HS - Ab deposition
Ab deposition fall in a linear fashion in binding to basement membrane of kidneys
SMOOTH
Multiple sclerosis
Type IV disease
T cells can invade BBB and cause immunity to myelin = attack myelin sheath
What does IFN-b do in MS?
halt plaques from progressing
Diagnostic for MS
IgG also seen in CSF
Presentation of MS
Females 10x more 20-30 y/o HLA-DR2 (rr=4.8) Motor weakness, impaired vision, lack of coordination, spasticity start with double vision
Diagnostic for MS
MRI - start to see sclerotic plaques
oligoclonal IgG
Mechanism of MS
Tdth cells infiltrate the CNS (white matter) and react with myelin basic protein
What are sclerotic plaques in MS?
Contain plasma cells that secrete oligoclonal IgG in CSF
MRI - start to see sclerotic plaques
Mechanism Ankylosing spondylitis
Antibodies formed in response to Klebsiella, Shigella or Yersinia react with spine, eventual fusion of spine
Which HLA associated with ankylosing spondylitis
B27
Reiter’s syndrome
Cross reacting antibodies to many STD’s (Arthritis, conjunctivitis, and fever) also see urethritis
What are the pro inflammatory cytokines?
IL-1, IL-6, and TNF-a
What is the triad for Reiter’s syndrome)?
- post infectious (STD and enteric)
Chlamydia, Yersinia, Shigella
are identifying triad for Reiter’s syndrome
Presentation of AS
Male 3x more
HLA - B27
“bamboo spine”
Relationship between AS and TB
Suppressing inflammatory response in AS can lead to TB spread
Sx of Reiter’s
joint stiffness, primarily involving knees, ankles, and feet (WRISTmay be early target)
Tx of Reiter’s
NSAIDs
COX-2 inhibitors
Experimental therapeutic approaches
T cell vaccination
Peptide blockage of MHC
Monoclonal Ab
T cell activation as experimental therapy
Vaccine against the antigens on T cell that attack other type of cells
vaccinate with autoimmune cells
Immune response is directed toward the TCR region of the autoimmune clone
Peptide blockade of MHC
MHC specific for self peptides
Synthetic peptides with 1 aa changed, binds better to MHC and out competes self peptides
prevent immune response
Monoclonal Ab
Anti-CD4, Anti-TCR, anti-MHC, and anti-IL-2R
will act to suppress function
Rationale for peptide blockage of MHC?
Some cells bind self peptide with higher affinity
DR4 – higher affinity than self – outcompete for the protein binding ?
Self peptide will need to compete for space
