Lecture 30: Autoimmunity & Autoimmune Diseases Flashcards
autoimmune disease happens when antigen-specific immunity targets _____ proteins
self
autoimmunity is generally a failure of _____ and ____ tolerance
central and peripheral
what effects can autoimmune diseases have on organs?
can damage them and when they try to repair themselves, it often leads to fibrosis or desposition of inflexible tissue that interferes with normal function
what does it mean if an autoimmune dx is organ-specific? What about if its systemic?
Organ Specific: the target antigen is unique to a given organ
Systemic: The autoimmune response is to a broad range of self-antigens
what are the 3 main ways autoimmune dx happen?
- autoreactive T cells and cell-mediated immune responses
- autoantibodies
- sometimes both
autoimmune dx affect ___% of the population
8
autoimmune dx are more common in what sex?
femail
what are2 reasons why females may have a higher chance of autoimmune dx?
- tendency of women to mount more robust innate & adaptive immune responses (except during pregnancy)
- immune-enhancing effects of estrogen (androgens promote immune suppression)
during pregnancy, Th__ responses are favoured rather than Th__
2; 1
what types of autoimmune dx may be worsened by pregnancy? Which ones may be ameliorated?
Th2 dx like SLE may be worsened; Th1 like MS may be improved
what are the immune effector cells in Type 1 DM?
Th1 cells and autoantibodies
what are the target of Myasthenia gravis?
acetylcholine receptors
what are the effectors of myasthenia gravis?
auto-antibodies (blocking)
what are the targets of MS?
brain or white matter
what are the effectors of MS?
Th1 and Tc cells and auto-antibodies
what are the targets of rheumatoid arthritis?
connective tissue, IgG
what are the effectors of rheumatoid arthritis?
auto-antibodies, immune complexes
what are the targets of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome?
Multiorgan/loss of FoxP3 gene
what are the targets of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome?
missing regulatory T cells
what are the targets of autoimmune polyendocrine syndrome type 1 (APS-1)
multiorgan loss of AIRE gene
what are the effects of autoimmune polyendocrine syndrome type 1 (APS-1)
defective central tolerance
In organ-specific autoimmune dx, ____ and ____ bind to cell membrane antigens, causing cell lysis and/or an inflammatory response that damages the target organs
lymphocytes or auto-antibodies
why is organ-specific localized to only that specific organ?
bc the antibodies/T cells bind only to the antigens present in that region
what are the target antigens of vitiligo?
melanocyte antigens
what is the immune pathology of Type 1 diabetes?
caused by cell-mediated autoimmune response to pancreatic beta cells in the islets of langerham. Activated CTL attack the beta cells, IFN-y, IL-1 and TNF-a are produced, leading to a DTH response . Autoantibodies may also contribute to islet cell destruction
what are the Sx and outcomes of Type 1 diabetes?
glucose metabolism is disrupted, leading to impeded blood flow, kidney failure, blindness, and death if untreated
what is the immune pathology of myasthenia gravis?
results from production of auto-antibodies directed against acetyl choline receptprs (AChR) on the motor end plates of muscles
what are the signs and outcomes of myasthenia gravis?
fatgable weakness and progressive weakening of structural muscles and evential death of ACh-R bearing cells. Severity ranges from droopy eyelid to life-threatening breathing difficulties due to myasthenic crisis
what is the treatment of myasthenia gravis?
removal of antibodies by plasmapheresis, suppression of B cell activation with corticosteroids and/or using cholinesterase inhibitors to increase Ach level
the hallmark of systemic autoimmune dx is damage throughout the body, which can present as _____ or ______
cell mediated immune reactivity or deposition of antibody-antigen complexes (or both)
what are some examples of systemic autoimmune Dx?
MS, SLE, RA
what is the immune pathology of Rheumatoid arthritis (RA)?
multifactorial, caused by autoantibodies of the IgM class (rheumatoid factor) that react with Fc of self IgG. The IgM/IgG complexes deposit in the synovia of the joints where complement is activated
what are the symptoms of RA?
chronic inflammation of the joints characterized by granulocyte/monocyte infiltration, cartilage/collagen destruction by hydrolytic enzymes, fibrin deposition and joint dysfunction
what are the outcomes of RA?
Can lead to life-threatening severities if left untreated, including cardiac involvement
what are the treatments for RA?
corticosteroids (to globally reduce immune activity), DMARDs, biologics (i.e. antibodies against TNF, IL-1B and IL-6 or the IL-6 receptor)
what is the immune pathology of MS?
demyelination of CNS nervous system tissue driven by CD4+ Th17 cells that attract & activate macrophages, leading to damage of nerve fibers, autoreactive CTL and antibodies
what are the symptoms of MS?
numbness, vision loss, paralysis, bladder & bowel dysfunction
t/f the recovery from MS attacks can be partial or complete
t
what are the outcomes of MS?
dictated by the degree of disease activity, location of attacks and dx-modifying therapies
what are the treatments for MS?
drugs to prevent lymphocyte egress into CNS, sequestration in lymphoid organs, anti-inflammatory agents, T & B cell depleters
_____ is a rodent model of central nervous tissue inflammation resembling MS in which T cell tolerance to myelin basic protein (MBP) or proteolipid protein components of the myelin sheath is broken by immunization with MPB in complete Freud’s adjuvant
experimental autoimmune encephalomyelitis (EAE)
autoimmune polyendocrine syndrome type-1 (APS-1) results from mutations in the ____ gene
AIRE
what is the purpose of the AIRE gene?
codes for AIRE transcription factor that allows tissue-specific antigens to be expressed in the thymus
what is the significance of the AIRE transcription factor allowing tissue specific antigens to be expressed in the thymus?
ensures elimination of autoreactive T cells and selection of Treg cells
immune dysregulation, polyendrocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in the _____ gene associated with ___ and ___ cells
FoxP3; tTreg cells & pTreg cells
AIRE and IPEX impact multiple organs and are characterized by what effects?
endocrine dysfunction, autoimmunity & primary immunodeficiencies resulting from disruption of immunologic homeostasis
autoimmune dx are often associated with expression of ___ molecules with certain allelic specificities
HLA
people with HLA-B27 are 100x more likely to develop _____ than people who have a different HLA-B allele
alkylosing spondylitis (autoimmune dx involving inflammtion of the vertebrae)
autoimmune dx are associated with preferential expression of certain TCR ____ region genes and mutations in ____ or ___ genes involved in establishing/maintaining tolerance
variable; AIRE or IPEX
people with ___ Treg cells, ____ TCR and MHC molecules capable of binding ____ will be susceptible to autoimmune dx
dysfunctional/low; autoreactive; self-peptides
inflammation-promoting environmental and/or lifestyle factors predispose people to autoimmune dx. Give some examples of these exposures
gum dx, smoking, vitamin D exposure
t/f infections and altered gut microflora are also complicated by induction of autoimmunity
t
in most cases, organ-specifc and systemic autoimmune dx is linked to what type of T cells?
autoreactive CD4+ T cells
aside from autoreactive CD4+ Tcells, what other T cells are involved in autoimmunity?
Th17 and Th1
what is the role of Th17 cells in autoimmunity?
produce Il-17 and IL-23
what is the role of Th1 cells in MS?
myelin basic protein (MBP)-reactive Th1 clones transfer autoimmune encephalomyelitis (EAE) to healthy mice
what is the role of Th2 cells in MS?
MBP-reactive Th2 cells prevent EAE induction by immunization with MBP
t/f many mechanisms for generation of autoimmune dx have been proposed. They are not mutually exclusive and any one or multiple could contribute
t
what are 4 proposed mechanisms of autimmunity?
- release of sequestered autoantigens
- inappropriate expression of MHC class II molecules and costimulation
- polyclonal B cell activation
- molecular mimicry
explain the “release of sequestered autoanitgens” theory of autoimmunity
accidental exposure of the immune system to autoantigens that are normally sequestered from immune cells are not negatively selected during development (i.e. lens protein, myelin basic protein)
explains the “inappropriate expression of MHC class II molecules and co-stimulation” theory of autoimmunity
- IFN-y production in response to trauma/viral infection can promote autoimmune dx by inducing class 2 MHC expression by unusual cells
- IFN-y also promotes IL-1, which can costimulate autoreactive T helper cells that react to the autoantigen in the MHC2
what are 4 examples of polyclonal B cell activators?
- LPS
- Gram-negative bateria
- cytomegalovirus
- Epstein Barr virus
polyclonal B cell activation can cause auto-antibodies of what class? They are secreted in the absence of ___ cells
IgM; autoreactive T helper cells
explain the “molecular mimicry” theory of autoimmunity
certain pathogens express molecules that closely resemble self-antigens and can therefore induce autoimmunity
many viral peptides are homologous with certain self antigens, such and ____ (virus) and ____ (self-antigen)
measles virus P3 & myelin basic protein (MBP)
____ type infection may be an initiating factor for development of some autoimmune dx
viral
explain plasmapheresis as a treatment for autoimmune dx
removes autoantibodies and immune complexes from the plasma & may provide temporary relief form sx of autoantibody-mediated autoimmune dx such as RA and myasthenia gravis
what is the role of immunosuppressive drugs like cyclosporin A in autoimmunity?
reduce severity of T-cell mediated autoimmune dx but leave the patient at greater risk for infection or cancer
antibodies that deplete ____ or ____ cells, or that target ____ molecules can reduce the sx of some autoimmune dx
T or B cells; chronic inflammatory molecules like TNF-a and adhesions molecules
oral administration of potential autoantigens such as myelin basic protein has been shown to induce ___ . How?
tolerance in animal models of dx, possibly by induction of pTreg cells that make immunosuppressive TGF-beta
targeted treatments can involve what 2 things?
- peptide blockage of TCR that recognize self-antigens/class 2 MHC
- give MAB that target activated autoreactive T cells
what MAB can be used in targeted therapy?
antibodies against the CD25 subunit of the high affinity IL-2 receptor
targets immunotherapy by vaccinating with autoreactive T helper cells has the potential to induce ____ antibodies that suppress the activity of dx-causing ____ cells, while sparing ____ cells
anti-TCR antibodies; autoreactive T cells; T cells with other antigenic specificites
