Autoimmunity Flashcards
(37 cards)
1
Q
What is autoimmunity, and what is it caused by?
A
- damage to self-cells caused by auto-antibodies/ T cells/ both
- caused by failure of tolerance processes
2
Q
What are some general features of autoimmunity?
A
- can be organ-specific or systemic
- up to 8% of population is affected
- Hashimoto’s thyroiditis > first organ-specific autoimmune disease characterized
3
Q
What is the main difference between organ-specific/ systemic autoimmune diseases?
A
Organ-Specific- immune response usually directed to target antigen unique to a single organ > manifestations largely limited to that organ
Systemic- autoreactive cells recognize target antigen in multiple tissues/ organs > inflammation/ physiologic disruptions at multiple locations in body
4
Q
How are the cells of target organs damaged in organ-specific autoimmune diseases?
A
- cells of target organ may be damaged directly by humoral/ cell-mediated effector mechanisms
- alternatively, anti-self antibodies can overstimulate/ block normal functions of target organ
- cell lysis/ inflammatory response in affected organ > fibrosis
5
Q
What drives tissue damage in systemic autoimmune diseases?
A
- cell-mediated immune activity
- auto-antibodies
- accumulation of immune complexes
6
Q
What are 3 organ-specific autoimmune diseases?
A
- Hashimoto’s thyroiditis
- Type 1 diabetes (insulin-dependent diabetes mellitus/ IDDM)
- Myasthenia gravis
7
Q
What are 3 systemic autoimmune diseases?
A
- Lupus
- Multiple sclerosis
- Rheumatoid arthritis
8
Q
What happens in Hashimoto’s thyroiditis?
- organ-specific autoimmune disease
A
- autoantibodies/ TH1 cells specific for thyroid antigens are produced
- resulting DTH response is characterized by thyroid gland infiltration by lymphocytes/ macrophages/ plasma cells
- these cells form lymphocytic follicles/ germinal centers > leukocytes can spontaneously form lymph-node-like assemblies (tertiary lymphoid organs)
- local inflammatory response caused by antibodies against thyroid-specific proteins causes a goiter
9
Q
What is a condition associated with Hashimoto’s thyroiditis?
A
Hypothyroidism
- autoantibodies against several thyroid proteins (thyroglobulin/ thyroid peroxidase) > interferes with iodine uptake > leads to hypothyroidism
10
Q
What is a treatment for Hashimoto’s thyroiditis?
A
- replacement therapy > daily administration of thyroxine
- allows patients to live a normal life
11
Q
What happens in type 1 diabetes?
- organ-specific autoimmune disease
- type 2 diabetes is not autoimmune
A
- autoimmune attack against insulin-producing beta cells in pancreas
- results in decreased production of insulin > increased levels of blood glucose
- starts with CTL infiltration/ activation of macrophages > insulitis > leads to cell-mediated DTH response > cytokine release/ production of auto-antibodies
- beta cell destruction mediated by cytokines released during DTH response/ lytic enzymes released from activated macrophages/ auto-antibodies specific for beta cells > ADCC/ antibody-mediated complement lysis
12
Q
What immune effectors mediate type 1 diabetes? (IDDM)
A
- starts with CTL infiltration/ activation of macrophages > Insulitis
> leads to cell-mediated DTH response
> resulting cytokine release/ production of auto-antibodies - subsequent beta-cell in pancreas destruction is mediated by…
> cytokines released during DTH response
> lytic enzymes released from activated macrophages
> auto-antibodies specific for beta cells > facilitate antibody-mediated complement lysis/antibody-dependent cell-mediated cytotoxicity
13
Q
What is one of the best-studied animal models of T1D, and what are some features of this model?
A
- NOD mouse spontaneously develops form of diabetes that resembles human T1D
- disease involves lymphocytic infiltration of pancreas/ destruction of beta cells
- strongly associated with certain MHC alleles
- mediated by bone-marrow-derived cells
> normal mice injected with bone marrow cells of NOD mice develop diabetes
> healthy NOD mice injected with bone marrow from MHC-matched normal mice do not develop disease - NOD mice housed in germ-free environments > higher incidence of diabetes than those in regular housing
14
Q
What happens in myasthenia gravis?
- organ-specific autoimmune disease
A
- autoimmune disease mediated by blocking antibodies
- type II hypersensitivity reaction
- auto-antibodies bind to ACh receptors on motor end plate of muscles
> block binding of ACh > induce complement-mediated lysis of cell - results in progressive weakening of skeletal muscles
- binding of auto-antibodies to AChR blocks normal binding of ACh
15
Q
What are treatments for myasthenia gravis aimed at?
A
- increasing ACh levels
- decreasing antibody production
- removing antibodies
16
Q
What happens in lupus?
- systemic autoimmune disease
A
- auto-antibodies bind to cells/ cellular components (DNA/ histones/ clotting factors/ RBCs/ platelets/ leukocytes)
- immune complexes of auto-antibodies/ nuclear antigens deposit along walls of small blood vessels > type III hypersensitivity reaction
- results in complement activation (MAC/ C3a/ C5a) > damage blood vessel walls > vasculitis
17
Q
What are the signs and symptoms of lupus?
A
- fever/ weakness/ arthritis/ kidney dysfunction/ skin rashes > characteristic butterfly rash across nose and cheeks
18
Q
What happens in multiple sclerosis?
- systemic autoimmune disease
A
- production of autoreactive CD4+ T cells
- TH17 cells and IL-17 they secrete is disease hallmark
- these T cells recruit other cells to site > inflammatory foci along myelin sheath in brain/ spinal cord
- leads to breakdown of myelin sheath > neurologic dysfunctions
19
Q
What genetic/ environmental associations does MS have?
A
Genetic- alleles at DRB1 locus of MHC II/ many other loci
Environmental- relocation from low to high incidence regions during early years > higher risk
20
Q
What is a rodent model for MS?
A
EAE- mediated solely by T cells
- induced by immunization with MBP (myelin sheath components)
- cellular infiltration of CNS > demyelination/ paralysis
21
Q
What happens in rheumatoid arthritis (RA)?
- systemic autoimmune disease
A
- production of antibodies that react with citrullinated protein antigens
- production of auto-antibodies called rheumatoid factors (RFs)
> RFs are specific for Fc region of IgG - immune complexes formed by binding RFS to normal circulating IgG are deposited into joints
> activates complement cascade > type III hypersensitivity/ chronic inflammation
22
Q
What is RA associated with?
A
- HLA-DRB1 locus (like MS)/ many non-MHC genes
- RA associated with smoking/ bacteria that causes gingivitis
> association not causation - environmental triggers may influence levels of citrullinated proteins in mucosa > triggering production of anti-self antibodies
23
Q
What are 2 genes with a major role in establishing/ maintaining tolerance?
A
- AIRE- TF critical for central tolerance in thymus > ensures tissue-specific antigens are expressed on mTECs in thymus during T cell development > ensures both elimination (negative selection)/ engagement (selection of regulatory T cells)
- FoxP3 is master TF associated with regulatory T cells (both tTregs/ pTregs) > both central/ peripheral tolerance
24
Q
What are 2 systemic autoimmune syndromes caused by disruptions in immune regulation?
A
- APS-1 > caused by mutation in AIRE gene (required for mTECs to display tissue-specific antigens)
- IPEX > caused by mutation in FoxP3 gene (required for T cells to become Tregs)
- APS-1/ IPEX are monogenic/ systemic/ have same range of immunopathologies (autoimmunity/ immune deficiency/ endocrine dysfunction)
> absence of Tregs/ disruption to self-tolerance
25
How can disruption to a single gene result in both too much immune response (autoimmunity) and not enough (immune deficiency)?
- absence of AIRE > APS-1
> autoreactive T cells not eliminated > autoimmunity
> engagement can not occur > no Tregs > immunodeficiency
- absence of FoxP3 > IPEX
> Tregs can not be produced > immunodeficiency
> if no Tregs > higher chance to develop autoimmunity
26
How can intrinsic (genetic) factors favour susceptibility to autoimmune disease?
> associations not causations
- genetic variants of immune-related genes are associated with predisposition to most autoimmune diseases
> certain MHC alleles
> Immune-regulatory genes (AIRE/ FoxP3) > systemic autoimmunity
- many other genes associated with autoimmunity > cytokines/ signaling pathways/ costimulatory receptors/ adhesion molecules ext
27
What is a single gene that heightens susceptibility to several autoimmune disorders?
- mutant form of PTPN22 linked to T1D/ RA/ lupus
- PTPN22 dampens TCR signaling > affinity of interaction not enough to eliminate cells in thymus > self-reactive cells escape/ cause autoimmunity
28
How can extrinsic (environmental) factors favour susceptibility to autoimmune disease?
> associations not causations
- obesity/ smoking/ infection/ diet/ mucosal microflora associated with risk of autoimmune disease
- autoimmune diseases are more common in certain geographic locations/ climates
> gut microbes interact with immune cells/ regulate peripheral tolerance/ suppress autoimmune diseases
- mice in germ-free environments are more susceptible to autoimmune disease (no commensal microbes) > microflora is important to prevent autoimmunity
29
How can infections influence the induction of autoimmunity?
- infection may result in release of sequestered self-antigens that fosters immune activation rather than tolerance
- certain microbes may share features with self-components > resulting in activation of immune cells with cross-reactive potential
- may explain geographic disparities > environments where certain infectious agents thrive > infections are autoimmune triggers in right genetic background
30
What are the 3 categories of current therapies to treat autoimmune disease?
- broad-spectrum immunosuppressive treatments
- immunosuppression directed at specific cells/ pathways
- targeted immunotherapy > aims to guide host immune cells to a new more beneficial pathway
31
What are the 2 types of broad-spectrum therapies?
- Broad-spectrum immune suppressants
> strong anti-inflammatory drugs that suppress lymphocytes by inhibiting their survival and proliferation/ killing rapidly dividing leukocytes
> are not cures, but do reduce symptoms
> side effects: general cytotoxicity (kills rapidly dividing cells)/ increased risk of uncontrolled infection/ cancer development
- Organ/ toxic compound removal > can alleviate symptoms
> thymectomy in patients with myasthenia gravis
> plasmapheresis in patients with MG/ lupus/ RA > temporarily eliminates autoreactive antibodies/ immune complexes
32
What is a treatment strategy that targets a specific cell type?
- targeting B/T cells when antibodies/ immune complexes are involved in autoimmune pathology
> monoclonal Ab against CD20 (B-cell specific antigen) > short term benefit in patients with RA
> anti CD3 antibodies somewhat effective to treat T1D, but broad-spectrum immune suppression
> anti-CD4 antibodies reversed MS/ arthritis in animals but failed in humans as remove both CD4+ Tregs, not only effector cells
33
What are some therapies that block specific steps in the inflammatory process?
- since chronic inflammation is a hallmark of autoimmune disease > target individual steps in inflammatory process
- more targeted approach than broad-spectrum anti-inflammatories
- drugs block TNF-α (early mediator) > RA/ psoriasis/ crohns disease
- IL-1/ IL-6 receptor antagonists > RA
- statins lower serum CRP levels > inhibit proinflammatory cytokines
34
What are some therapies that interfere with co-stimulation (signal 2)?
> control T cell activation
- CTLA-4 is a potent inhibitor of T-cell activity
> binds to CD80/86 with greater affinity than CD28 (costimulatory counterpart)
- CLTA-4Ig fusion protein > blocks CD80/86 on APCs from engaging with CD28 on T cells > inhibiting costimulation
> approved for RA treatment
35
What is an example of antigen-specific immunotherapy?
- specifically inducing tolerance to auto-antigen
- GA polymer found in MBP > approved for treatment of MS
> shifts Th population to increase number of Tregs
36
What are the 5 main mechanisms of action of treatments for autoimmune diseases?
- T/B cell depleting agents
- targeting cell trafficking/ adhesion
- targeting TCR signaling
- targeting costimulatory/ accessory molecules
- targeting cytokines/ cytokine signaling
37
How does fingolimod work?
- compound that blocks adhesion molecule signals > controls lymphocyte movement into site of inflammation
- analog of sphingosine > binds to/ blocks sphingosine receptor > inhibits trafficking of T cells
