module 09 section 02 (autoimmune disease) Flashcards
autoimmune diseases are the result of?
overreactivity of the immune system against its own tissues
does the presence of anti-self antibodies or anti-self cell-mediated immunity always develop into an autoimmune disease?
not necessarily
are autoimmune diseases organ-specific or systemic?
can be either
autoimmune diseases affect what % of the population?
5-7%
autoimmune diseases have been linked to what? why?
certain MHC haplotypes - as they may fail to delete anti-self T-cells or B-cells
why is it important to always consider autoimmune disease when diagnosing?
- becuase there’s a wide range of non-specific symptoms
- they dont always present the same
- they’re shared between many other conditions
- they effect a lot of different body systems
- usually consider infectious/hemolytic conditions before autoimmunity
- e.g. lupus = fatigue, rash, arthritis
- why ask about family history - allergies/celiac can be indicators
recall: what is central tolerance?
mechanism by which the immune system learns to discriminate self vs non-self antigens
(lymphocytes with receptors to self-antigens are removed by apoptosis)
what provides the incentive for microorganisms to develop epitopes similar to proteins found within the host?
clonal deletion (how self-antigens are deleted - if resemble self - wont be attacked)
what is peripheral tolerance?
mechanism by which the body prevents over-reactivity of the immune system to various environmental factors
(e.g. allergens, gut microbes)
defects in central or peripheral tolerance may lead to what? why?
autoimmune diseases, as lymphocytes specific to seld antigen or some environmental factors remain in circulation
MHC class II presentation of self or forgein peptides can result in?
immunological tolerance
why have some HLA genes been associated with autoimmune diseases?
because of the role of MHC in antigen presentation
what does it mean for someone who has these specific HLA genes?
they have an increased relative risk for autoimmune disease
what is relative risk? how do you calculate it?
ratio of the probability of an event occuring with a specific MHC, compared to without the specific MHC
RR = (frequency of disease in patients with HLA) / (frequency of disease in patients without HLA)
how can the inheritance of AI diseases be determined clinically?
by HLA-typing (because some have been associated with specific HLA genes)
can HLA-typing for AI diseases be a factor in genetic counseilling/family planning?
yes
what specific HLA haplotype expression is 100x more likely to result in insulin-dependent diabetes (type I)?
DR3/DQW8
RR=100 for HLA DR3/DQW8
what specific HLA haplotype expression is 90x more likely to result in ankylosing spondylitis?
B27
RR=90 for HLA B27
do anti-self T-cells/B-cells in circulation need to be triggered to become activated?
yes
what are the 3 major mechanisms of triggering anti-self cells that result in autoimmune disease?
(1) molecular mimicry
(2) release of sequestered antigen
(3) polyclonal B-cell activation
what is molecular mimicry
- foreign antigens can have epitopes similar to those of self antigens
- so, an immune response for a foreign antigen may also result in the cross-activation of anti-self B/T-cells against self tissues with similar epitopes
- I.e. since the foreign antigen has similar (mimics) epitopes to the self-antigen, the immune response attacks both
streptococcus bacteria display similar epitopes to those expressed in the ______?
what is the result of this?
heart muscle - resulting in rheumatic carditis due to infection with the bacteria
what is rheumatic carditis characterized by? why?
cardiac inflammation and scarring
-result of cross reactivitiy of antibodies due to molecular mimicry of the strep antigen to the heart muscle antigens
what are two functions of B-cells that play a role in the development in autoimmunity?
- they produce antibodies
- they’re APC
list and explain 2 other autoimmune diseases that could result from antigenic mimicry
(1) multiple sclerosis - can be caused by epstein barr virus, human herpesvirus 6 and milk protein butyrophilin
(2) ankylosing spondylitis - antibodies against klebsiella can cross-react with HLA B27
what is important for antigenic mimicry
how the APC presents the antigen
explain what the release of sequestered antigens is
- recall: central tolerance = where lymphocytes are exposed to self antigens
- some self-antigens in immunologically priviledged sites such as brain, eye lens, cornea, spermatozoa and heart muscle are sequestered from the immune system
- in the event of trauma or infection these sequestered antigens can become exposed to the immune system, where they may be recognized as foreign, initiating autoimmune disease
what is sympathetic uveitis?
inflammation that occurs following accidental/surgical insult to the eye (clinical e.g. of sequestered antigen release)
what is the clinical presentation of sympathetic uveitis? (3) what does histopathology reveal?
- mutton-fat keratic precipitates
- choroidal infiltrations
- Dalen-Fuchs nodules
- histopathology = difuse infiltrations of the uvea/choroid by lymphocytes
explain polyclonal B-cell activation
- viruses (such as EPV and CMV) can activate mature B-cells to produce antibodies with different specificities
- this = greater chance of cross-reaction to different antigens, including different bacteria or self antigens (like rbcs or DNA)
- this can develop into autoimmune disease
- main takeaway = polyclonal activation leads to cross reactivity leads to AI disease
Epstein-Barr virus is the most common virus in the _____ family?
herpes family
EBV infection is transferred through?
saliva and gential secretions
what does EBV infect?
epithelial cells of the oropharynx
EBV is associated with cancers and other symptoms such as: (4)
Hodgkin’s lymphoma, Burkitt’s lymphoma, oral hairy leukoplakia (benign oral lesion) and massive tonsils
explain the detrimental effects of a persistent EBV infection
- virus can shift from active lytic cycle and latent state
- this enables evasion of the immune system and the initation of autoimmune disease (via polyclonal B-cell activation)
ankylosing spondylitis (AS) is an autoimmune disease with several characteristics which make it distinct from other autoimmune diseases.
which of the following is incorrect about AS?
(a) a high realtive risk (RR=100) for HLA DR3/DQW8
(b) the disease is more common in men than in women
(c) it’s beleived that the immune response to Klebseilla bacteria may be involved in the pathogenesis of the disease
(d) its an example of autoimmune disease in which antigenic mimicry may be involved
(e) the disease often starts with arthritis in the lower back
(a) a high relative risk (RR=100) for HLA DR3/DQW8
this is true for type I diabetes, the relative risk for AS is RR=90
compare what’s involved in organ-specific vs systemic autoimmune diseases
organ specific = an immune response against self-antigens of a single organ
systemic = an immune response against self-antigens throughout many tissues
list an organ specific autoimmune disease for:
- thyroid
- stomach
- neuromuscular junction
- pancreas
- thyroid: Grave’s disease
- stomach: pernicious anemia
- NMJ: myasthenia gravis
- pancrea: insulin dependent diabetes
list a systemic autoimmune disease for:
- muscle
- DNA, RNA
- joints
- skin
- muscle: dermatomyositis
- DNA, RNA: systemic lupus erythematosus
- joints: RA
- skin: scleroderma
what is pernicious anemia?
the absence of intrinsic factor - typically causing the stoamch lining to shrink
(intrinsic factor = protein secreted by stomach lining cells - helps with absorbtion of Vit. B12)w
what is dermatomyositis?
inflammatory muscle disease that causes muscle weakness and is associated with skin rash
what is scleroderma?
rare, chronic disease characterized by excessive deposits of collagen, causing thickening of the skin
what is myathenia gravis?
chronic autoimmune disease - results from antibodies against nicotinic Ach receptors at the neuromuscular junction, preventing Ach from binding, preventing muscle contractions
what is myathenia gravis treated with? why?
- acetylcholinesterases (degrades excess Ach in junction) inhibitors
- high [Ach] in the synaptic cleft increases the likelihood of Ach binding to its receptor to stimulate muscle contraction
what are two clinical signs of myathenia gravis? do they go away after treatment with AChE inhibitors?
- muscle weakness
- drooping eyelids (ptosis) = hallmark
- significant improvement with AChEi
what is Grave’s disease?
AI disease that often manifests as hyperthyroidism due to antibodies against (that chronically stimulate) the TSH receptor
generally explain the hypothalamic-pituitary-thyroid axis
- TRH released from hypothalamus
- TRH stimualtes TSH release from pituitary
- TSH stimulates thyroid gland to produce T3 and T4
- T3 and T4 stimulate metabolism in body tissues
- excess circulating T3/T4 stimulates thyroxine receptors in the pituitary gland to supress the release of additional TSH
- low circulating T3/T4 promote TSH release, further promoting T3/T4 production
what is the hallmark symptom of Grave’s disease?
what are other symptoms? (2)
- hallmark = goitre - swelling of the neck resulting from enlargement of the thyroid gland
- bulging eyes
- muscle weakness
what type of antibodies are involved in Grave’s disease?
what are the implications of this?
IgG - can cross placenta and cause neonatal Grave’s disease (aka neonatal thyrotoxicosis)
what is Goodpastures syndrome? what does it affect?
AI disease where antibodies attack the basement membrane of lung alveoli and glomerulus in the kidney
is Goodpastures syndrome serious? why?
talk about pathophysiology
- circulating anti-glomerular basement membrane (anti-GBM) antibodies bind to epitopes on the basement membrane and activate complement cascade
- leads to bleeding from the lungs and kidney failure
- results in immediate tissue injury
what is systemic lupus erythematosus?
- the body makes anti-nuclear and anti-cytoplasmic antibodies
- immune complexes are diposited in different tissues, ultimately triggering inflammation
- inflammation can result in conditions such as arthritis, carditis, dermatitis, vasculitis and glomerulonephritis
what is rheumatoid arthritis?
- AI disease that primarily affects the joints
- mediated by T-cells and/or antibodies
what is the mechanism for rheumatoid arthritis development mediated by T-cells?
- when Th1 cells engage with a specific antigen in the joints, they release cytokines that initate local inflammation
- leukocyte recruitment causes damage to the cartilage in the joint leading to its destruction
what is the mechanism for rheumatoid arthritis development mediated by antibodies?
- involves rheumatoid factor (RF) which is an IgM anti-IgG autoantibody (immune complex)
- these immune complexes deposit in the joints and bvs and are associated with destructive inflammation
in rheumatoid arthritis, RF factors isolated from joints show evidence of what?
a T-cell dependent B-cell response against the Fc portion on the IgG
which of the following conditions is assoicated with a rise in serum anti-self antibodies due to polyclonal B-cell activation?
(a) allergy to penuts
(b) pemphigus
(c) myocardial infarction
(d) Grave’s disease
(e) infectious mononucleosis (EBV)
(e) infectious mononucleosis (EBV)
many normal individuals have detectable antibodies against a number of self antigens. This is much more common in patients with AIDS and infectious mononucleosis, due to infection with EBV.
which one of the following cell types can be polyclonally activated by EBV?
(a) NK cells
(b) mast cells
(c) monocytes
(d) B-cells
(e) T-cells
(d) B-cells
