Tolerance and Immunology Flashcards
Tolerance
process by which the body ensures that immune responses are directed against foreign antigens and altered self and not against normal self tissues
Tolerance definition
SPECIFIC unresponsiveness of an individual to an antigen
Which cells are capable of tolerance
only cells with antigen-specific receptors can be tolerant… B and T cells
Tolerance mechanism involves
the selective destrcution of lymphocytes that react to self antigens (positive and negative selection)
Central tolerance
occurs early in lymphocyte development
Peripheral tolerance
regulation of “escapees” of central tolerance in the periphery
Central B tolerance
if an immature B cell possesses an IgM that is self-reactive it will undergo anergy (tolerant signals) ro deletion (apoptotic signals)
Peripheral B cell Tolerance
BCR is constantly stimulated, chronic stimulation in the absence of other secondary signals = anergy
Central T cell Tolerance
if an immature T cell possesses a TCR that is strongly self-reactive, apoptosis is induced
Peripheral T cell Tolerance
Primary stimulation of Tcells (antigen recognition) without secondary stimulation results in an inactive T cells
Primary stimulation of peripheral T cells
antigen recognition via MHC/peptide-TCR
Secondary stimulation of peripheral T cells
B7-CD28 stabilizes IL-2 mRNA that is otherwise rapdily degraded
Antigen recognition without _____________ results in
IL-2 present results in peripheral T cell anergy
Repeated stimulation of activated T cells results in
apoptosis (clonal deletion)
Regulatory T cells
inhibits the activation of T cells by self peptide/MHC
Peripheral Tolerance via regulatory B cells
produce IL-10 that negatively regulates the activation of both Th1 CD4+ T cell and CD8+ T cells
Peripheral Tolerance via regulatory T cells
CD4+ usually (may be CD8+), express FoxP3, secrete inhibitory cytokines (TGF-beta, IL-10 for Th1 inhibition) and CTL lysis
FoxP3
transcriptional repressor expressed by T reg and B reg cells
relapsing MS patients show
decreased numbers of IL-10 producing B cells and decreased ability of existing cells to produce IL-10
What age groups are consider immunosuppressed
very young and elderly
malnutrition may
play a profound effect on the immune system
Disease
some diseases may induce a state of nonresponsiveness to antigens
Stress
profoundly affects the immune system
HLA sequence
determines whether a individual will be capable of responding to an antigen sequence
HLA-B27
HLA sequence that causes autoreactivity producing ankylosing spondylitis and reactive arthritis
Doasge and tolerance
small doses over long periods induce tolerance
If self molecules are located in immunologically privileged sites and trauma occurs
the immune system may gain access to “new” antigens evoking a response
Sympathetic opthalmia
retinal or uvealproteins exposed after trauma to eye
Genetic predisposition to autoimmunity
HLA type inheritance
Preceding infectious processes in autoimmunity
molecular mimicry from a pathogens antigens causes cross-reacting immune-responses
Streptococcal pharyngitis –> which autoimmune disease?
rheumatic fever and heart valve destruction
Helicobacter pylori –> which autoimmune disease?
gastric carcinoma
Campylobacter jejuni –> which autoimmune disease?
Guillian-Barre syndrome
What is Guillian-Barre syndrome
immune response against the pathogens LPS that cross-reacts with motor nerves, resulting in severe paralysis and polyneuritis
Klebsiella –> which autoimmune disease?
ankylosing spondylitis (chronic inflammation, fibrosis, and ossification of the articulations)
Diseases that elicit polyclonal activation of lymphocytes act via
activation of previously anergic self-reactive lymphocytes
What factors are linked to autoimmune diseases?
genetics, previous infection, environmental trigger,impaired immunoregulatory mechanisms, hormones/gender
Environmental triggers linked to autoimmune diseases?
exposure to environmental triggers (ie. gluten)
Exposure to gluten may lead to
Celiac Disease
What is Celiac Disease
exposure to gluten causes autoimmune attack on villi in the small bowel (villi atrophy and T cell infiltration)
Celiac Disease is mediated by
T cells
95% of individuals with Celiac Disease have
autoantibodies against tissue transglutaminase (anti-TG)
90% of individuals with Celiac Disease have
HLA-DQ2 and remaining have HLA-DQ8
Celiac Disease is associated with
IgA deficiency
Impaired immunoregulatory mechanisms that lead to autoimmune diseases
deficient or defective T cells may alter normal immune control, defective antibody production of one class may lead to inhibition of another class
Example of defective antibody production of one class may lead to inhibition of another class
elevated IgE in selective IgA deficiency
Which gender is more likely to have an autoimmune disease and why
women, possibly due to ER on immune cells
Myasthenia Gravis is a result of
antibodies produced against the ACh receptors at neuromuscular junctions (ORGAN-SPECIFIC)
Myasthenia Gravis manifestations
severe muscle weakness, drooping eyelids, difficulty chewing, swallowing, breathing
Myasthenia Gravis genetic component
associated with HLA-DR3
Myasthenia Gravis
Organ-specific, antibody-mediated
Autoimmune hemolytic anemia is the result of
antibodies produced against either Rh antigen or I antigens on RBCs, targetting them for destruction
RBCs in Autoimmune hemolytic anemia
complement-mediated lysis or macrophage phagocytosis
Autoimmune hemolytic anemia effects which body system
spleen (organ-specific)
Autoimmune hemolytic anemia manifestations
anemia, haemolysis, low haptoglobin, increased lactate DH, elevated direct bilirubin
Myasthenia gravis is a Type ____ hypersensitivity
Type II
Direct antiglobin would test positive in which disease
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia is caused by
warm hemagluttinins or cold hemagluttinins
Warm hemagluttinins
IgG that can bind RBCs at 37C specific for Rh (Kupffer phagocytosis)
Cold hemagluttinins
IgM binds RBCs at less than 37C specific for I antigens (complement/MAC)
Systemic Lupus Erythematosus
antibodies against double-stranded DNA (and other nuclear/cytoplasmic components) form IC and deposit in kidneys, arteriole walls, synovium
Systemic Lupus Erythematosus IC’s activate
complement, PMNs, granulocytes
Systemic Lupus Erythematosus manifestations
fever, joint pain, malar, CNS damage, damage to heart and kidneys
genetic component of SLE
C1, C4, or C2 deficiency resulting in lack of C3b for IC phagocytosis
Systemic Lupus Erythematosus is more common in what patient population
women 15-45
is linked to what HLA type
HLA-DR3 or DR2
Tests for Systemic Lupus Erythematosus
indirect fluorescent antibody stain
Scleroderma
antibody production against nuclear enzymes (topoisomerase and RNA pol)
Scleroderma manifests as
skin thickening, arthritis, hair loss, arteritis, Reynaud’s, overproduction of EC matrix proteins
Scleroderma is most common in what patient population
women 30-50
Sjogren’s Syndrome
antibodies against cytoplasmic protein-RNA complexes called SS-A (Ro) and SS-B (La)
Detection of Scleroderma
indirect fluorescent antibody stain (same as SLE) but different pattern
Sjogren’s Syndrome manifestation
systemic inflammation and destruction of exocrine glands, esp salivary and lacrimal - dry mouth and eyes
Sjogren’s Syndrome detection
ELISA or western
SLE is a Type _____ hypersensitivity
Type III
Graves’ Disease
antibodies (TSI) against TSH receptors, bind and cause expression of TSH receptor = hyperthyroidism
Graves’ Disease Manifestations
low TSH, high T4 and T3
TBIIs
antibodies aginst TSH receptors, bind and cause repression og TSH receptor = hypothyroidism
Graves’ Diseaseeffects primarily
women (4:1)
Goodpasture’s Disease
antibody production against alpha-3 chain of basement membrane collagen, Fc binds Fc-gamma receptors on immune cells for activation
Goodpasture’s Disease manifestations
binding to renal glomeruli, pulmonary alveoli causing disease and tissue injury
Goodpasture’s Disease is a Type _____ hypersensitivity
Type II
Multiple Sclerosis
T-cell mediated (CD4 and CD8) response to CNS myelin
MS may be linked to
EBV, ADV-2, Hep-B infections, and associated with HLA-DR2
Type I DM
T-cell mediated- CD8 CTLs destroy insulin-producing beta cells of the pancreas
Genetic component to Type I DM
HLA-A2
Rheumatoid Arthritis
T-cell mediated and antiboy mediated
Inflammation in RA in initiaed by
deposition of IC’s and inflammaotry infiltration of the synovial membrane
What immune cells are present in RA synvoial membranes
macrophages, T cells, and plasma cells
RA manifestations
chronic inflammation of the synovium, fever, fatigue, joint pain and swelling
Pannus
destruction of neighborign cartilage to expose chondrocytes and compromise synvoial integrity
2 diagnostic markers for RA
anti-citrullinated peptide antibodies (ACPAs) and rheumatoid factor (RF)
RF
IgM against IgG Fc portions, form IC’s that are deposited in the synovium –> complement
RF titers
20-30% of the time, no RF in RA patients, but generally RF levels coincide with RA severity
presence of RF and arthritis
not always due to RA, RF may be elevated in SLE
ACPA titers
90-95% indication of RA
Hashimoto’s thyroiditis
T cell-mediated, but have antibodies against thyroid peroxidase and thyroglobulin
What type of hypersensitivity is Hasimoto’s?
Delayed Type IV
Hashimoto’s thyroiditis manifestations
puffy round face, dry skin, cold, brittle hair and nails
Hashimoto’s thyroiditisis associated with
HLA-DR5, -Dr3 and B8
Treatment for hypothyroidism
administration of thyroxine
Myasthenia Gravis treatment
cholinesterase inhibitors
immunosuppressive therapy for autoimmune disease
anti-mitotic drugs, anti-inflammatory, cyclosporine
advantages and disadvantages of using immunosuppressive therapy for autoimmune disease
dampen immune response, adverse side effects (susceptibility of disease), NSAIDS
Cytokine treatment of MS
IFN-beta.1a (avonex, rebif)
TNF-alpha blockades (infliximab, etanercept, adalimumab, golimumab, certolizumab
treatment for RA and akylosing spondylitis
SLE and scleroderma treatments
bone marrow ablation and transplant
glatiramer acetate
induces production of Treg cells for treatment of MS
tocilizumab
tocilizumab for RA Anti-IL-6R
rituximab
anti-CD20 for B cell targeting
abatacept
T cell activator for RA
natalizumab
anti-alpha-4 integrins for MS
Anti-BAFF
SLE
Low dose - Oral tolerance
oral low dose Ag causes induction of Th3 cells and the release of TGF-beta which inhibits Th1 and Th2
Low dose - Oral tolerance results
ag-specific Th3 and IgA isotype switch (inhibits Th1 and Th2 and cytokine production)
High dose - Oral tolerance
clonal exhaustion and anergy of CD4 T cells
Oral tolerance for MS
bovine myelin
Oral tolerance for RA
Type II collagen
Oral tolerance for graft rejection
HLA molecules
