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PABI 6100 Immunobiology- Exam > Autoimmunity > Flashcards

Autoimmunity Flashcards

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
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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
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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

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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
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5
Q

What drives tissue damage in systemic autoimmune diseases?

A
  • cell-mediated immune activity
  • auto-antibodies
  • accumulation of immune complexes
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6
Q

What are 3 organ-specific autoimmune diseases?

A
  • Hashimoto’s thyroiditis
  • Type 1 diabetes (insulin-dependent diabetes mellitus/ IDDM)
  • Myasthenia gravis
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7
Q

What are 3 systemic autoimmune diseases?

A
  • Lupus
  • Multiple sclerosis
  • Rheumatoid arthritis
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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
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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

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10
Q

What is a treatment for Hashimoto’s thyroiditis?

A
  • replacement therapy > daily administration of thyroxine
  • allows patients to live a normal life
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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
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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
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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
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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
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15
Q

What are treatments for myasthenia gravis aimed at?

A
  • increasing ACh levels
  • decreasing antibody production
  • removing antibodies
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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
Q

How can disruption to a single gene result in both too much immune response (autoimmunity) and not enough (immune deficiency)?

A
  • 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
Q

How can intrinsic (genetic) factors favour susceptibility to autoimmune disease?

> associations not causations

A
  • 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
Q

What is a single gene that heightens susceptibility to several autoimmune disorders?

A
  • 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
Q

How can extrinsic (environmental) factors favour susceptibility to autoimmune disease?

> associations not causations

A
  • 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
Q

How can infections influence the induction of autoimmunity?

A
  • 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
Q

What are the 3 categories of current therapies to treat autoimmune disease?

A
  • 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
Q

What are the 2 types of broad-spectrum therapies?

A
  • 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
Q

What is a treatment strategy that targets a specific cell type?

A
  • 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
Q

What are some therapies that block specific steps in the inflammatory process?

A
  • 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
Q

What are some therapies that interfere with co-stimulation (signal 2)?
> control T cell activation

A
  • 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
Q

What is an example of antigen-specific immunotherapy?

A
  • 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
Q

What are the 5 main mechanisms of action of treatments for autoimmune diseases?

A
  • T/B cell depleting agents
  • targeting cell trafficking/ adhesion
  • targeting TCR signaling
  • targeting costimulatory/ accessory molecules
  • targeting cytokines/ cytokine signaling
37
Q

How does fingolimod work?

A
  • 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

PABI 6100 Immunobiology- Exam (6 decks)

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