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Immunology 3115 > Immune Regulation and Autoimmunity > Flashcards

Immune Regulation and Autoimmunity Flashcards

1
Q

Self-limiting immune response

A

Immune response to forgein antigens diminishes as antigens are diminished

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2
Q

Role of antigen

A

Induces signals from antigen receptors, costimulatory molecules, cytokine receptors that promote survival of antigen-reactive lymphocytes

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3
Q

Bcl-2

A

Anti-apoptotic protein
Unregulated expression while antigen present
Decreased expression causes immune effector cells to become more susceptible to apoptosis without survival signals

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4
Q

Antigenic competition

A

Competing antigen can regulate immune response to an unrelated antigen
ie. Cytokine cross regulation during a co-infection of immuno-dominant Th1 stimulating infection and lesser Th2 stimulating infection, IFN-gamma form Th1 infection downregulated Th2

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5
Q

Role of antibody

A

Clearance of antigen by forming immune complexes that are phagocytosed by macrophages (elimination of antigen)
Feedback

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6
Q

Secreted IgG

A

Continued activation of B cells

Formation of immune complexes that cross-link surface Ig and IgG Fc receptors on B cells

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7
Q

Antibody feedback

A

IgG Fc receptor on B cells interacts with secreted IgG

Activation of phosphatase that prevents further signaling through BCR

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8
Q

Active regulatory mechanism

A
  1. CTLA-4
  2. AICD
  3. CD4+CD25+ Treg cells
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9
Q

CTLA-4

A

Expressed several days after T cell activation
Greater avidity for CD80/CD86 than CD28: favourably competes with CD28 for its ligands
Binding to B7 molecules deprives T cells of costimulatory signals through CD28, downregulating T cell activation

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10
Q

CTLA-4 mutant mice

A

Massive autoimmune T cell proliferation (in response to self antigen) and die within 4 weeks of birth

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11
Q

Activation-induced cell death (AICD)

A

Maintenance of T cell homeostasis
T cell activation causes expression of Fas and Fas ligand
Trimerization of Fas by Fas ligand on a neighbouring cell leads to T cell death by apoptosis

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12
Q

Fas/Fas ligand Mutant mice

A

Mutant mice that lack functional Fas or Fas ligand have excessive numbers of T cells
Spontaneously develop autoimmune disease

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13
Q

CD4+CD25+ T regulatory cells

A

Natural or inducible
Antigen specific
Inhibit proliferation of T cells by cell contact-dependent mechanism
Can increase/decrease activity to change immune responses
Produce products that inhibit cells around them: adenosine
Some kill using perforin and granzyme
Need to be close to target cells

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14
Q

Natural T regulatory cells

A

Arise in thymus and populate other lymphoid tissues

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15
Q

Inducible T regulatory cells

A

Arise in periphery after persistent antigenic stimulation of T cells

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16
Q

Adenosine

A

Binds to effector cells inhibiting proinflammatory activities

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17
Q

Treg interaction via CTLA-4

A

Interacts with CD80/CD85 on dendritic cells
Causes activation of signal pathways that cause expression of IDO, decreased expression of inflammatory promoting cytokines and costimulatory molecules

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18
Q

Indoleamine-2,3-dioxygenase (IDO)

A

Metabolizes extracellular tryptophan

Tryptophan deficient environment makes effector T cells die by apoptosis

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19
Q

Extracellular tryptophan

A

Regulator of activated T cells

Deficient environment causes effector T cells to die by apoptosis

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20
Q

Prostaglandins

A

ie. PGE2
Can be produced by macrophages
Inhibits immune responses in nonspecific manner
Promote cAMP accumulation in T cells, which inhibits IL-2 synthesis and receptor signaling

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21
Q

Anti-idiotype antibodies

A

Recognize antigen binding site of an antibody molecule that has a characteristic structure or formation

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22
Q

Idiotype

A

Sum of individual idiotopes of antigenic determinants that are located in and out of the antigen binding site

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23
Q

Idiotope

A

Antigenic determinant in variable region

May be located in or outside antigen binding site

24
Q

Idiotypic networks

A

Network of antibody, anti-idiotype, anti-anti-idiotype, etc

Complementary interaction between idiotypes and anti-idiotypes reach a steady state: homeostasis

25
Q

Anti-idiotype responses

A

Shut off antigen-specific (idiotype expressing) lymphocytes

26
Q

Tolerance

A

Mechanism to protect individuals from potentially self-reactive lymphocytes
Active state of specific immunologic unresponsiveness, with antigen specificity and memory, that is induced by prior exposure to an antigen
Failure to develop tolerance to self-antigens leads to autoimmunity

27
Q

Factors determining if antigen with stimulate immune response or promote tolerance (5)

A
  1. Tolerance is more easily induced in immature lymphocytes
  2. Given antigen must persist in host in order to promote/maintain tolerance
  3. Antigen introduced by oral or intravenous route tend to promote tolerance
  4. Induction is favoured by absence of adjuvants and/or low levels or costimulation
  5. Soluble antigens are more likely to induce tolerance than aggregated antigens
28
Q

Soluble vs. aggregated antigens and tolerance

A

Soluble is better because APCs that internalize soluble antigen may express costimulatory B7 family members

29
Q

Central tolerance

A

Deletion of self-reactive lymphocytes by apoptosis during maturation in bone marrow or thymus
Programmed cell death
T cells in thymus and B cells in bone marrow

30
Q

Peripheral tolerance

A

Inactivation of self-reactive lymphocytes in peripheral tissues
Not all self-antigens are present in the primary lymphoid organs
Certain antigens are hidden from potentially responsive lymphocytes: exposure can cause autoimmune disease
CTLA-4 and Fas/Fas ligand death (Treg) are involved

31
Q

Clonal anergy

A

Result of inability of most cells in the body to express costimulatory molecules
Self-reactive T cells that bind antigen via TCR in absence of costimulatory response become anergic to antigen upon subsequent exposure

32
Q

Autoimmune disease

A

Caused by defects in central and/or peripheral tolerance
5-7% of population affected
More women (more Th1-like immune responses)
Organ-specific or system
People with one autoimmune disorder are at greater risk for additional autoimmune issues
Associated with HLA allelic specificities
Associated with preferential expression of certain T cell receptor variable region genes
Most likely in individuals with MHC molecules and TCRs that are capable of binding self-peptides

33
Q

Organ specific immune disease

A

Target antigen is unique to given organ
Lymphocytes/antibodies bind to cell-membrane antigens, causing cell lysis/inflammatory response
Function of organ declines
Damaged tissue is replaced by scar tissue
Usually due to autoreactive CD4+ T cells

34
Q

Systemic immune disease

A

Autoimmune response to a broad range to antigens

35
Q

Insulin-dependent diabetes mellitusis

A

Caused by autoimmune response to insulin-producing beta cells located in islets of Langerhands within pancreas
Activated CTL infiltrate islets and attack beta cells
Proinflammatory cytokines, IFNgamma, IL1, TNDalpha, are produced that activate macrophages causing delated type hypersensitivity response

36
Q

Graves’ Disease

A

Autoantibodies directed against receptors in thyroid cells mimic effects of TSH
Cause activation of receptor-coupled adenylate cyclase, stimulating production of thyroid hormones
Thyroid is overstimulated, causing excessive production of thyroid hormones

37
Q

Rheumatoid arthritis

A 
System autoimmune disease
IgM class (rheumatoid factor) auto-antibodies that react with Fc portion of self IgG
IgM-IgG complexes are deposited in synovia of joints
Chronic inflammatory response
Infiltration of joints by granulocytes and monocytes,
Destruction of cartilage and collagen by hydrolytic enzymes
Deposition of fibrin
Joint fusion
38
Q

Multiple sclerosis

A

Demyelination of central nervous system by T cells - autoreactive T cells specific for myelin basic protein produce cytokines that attract/activate monocytes that do the damage
Autoreactive CTL and autoantibodies
Progressive paralysis
Lesions resemble cellular infiltrates characteristic of DTH reactions

39
Q

Th2 cells in autoimmunity

A

Can prevent induction of autoimmune disease

May halt progression of existing autoimmune disease

40
Q

EAE in mice

A

MBP-reactive Th1 clones transfer experimental autoimmune encephalomyelitis to healthy mice
MBP-reactive Th2 cells prevent EAE induction by immunization with MBP
Tolerance to MBP is broken by immunization with MBP in complete Freud’s adjuvant

41
Q

HLA-B27

A

Individuals with this allele of HLA are more likely to develop anklyosing spondylitis than those with another HLA-B allele

42
Q

Ankylosing spondylitis

A

Autoimmune disease involving inflammation of the vertebrae

43
Q

Mechanisms of autoimmune disease induction (4)

A

Several, not mutually exclusive

  1. Release of sequestered autoantigens
  2. Molecular mimicry
  3. Inappropriate expression of Class II MHC molecules
  4. Polyclonal B cell activation
44
Q

Mechanisms of autoimmune disease induction: release of sequestered autoantigens

A

Accidental exposure to autoantigens that are normally sequestered from circulation and not encountered by T cells in thymus
Can result in autoimmune disease as lymphocytes were not rendered tolerant
ie. lens protein, MBP

45
Q

Mechanisms of autoimmune disease induction: molecular mimicry

A

Pathogens expressing molecules that closely resemble self antigens may induce autoimmunity, many virual proteins are homologous with certain self-antigens

ie. T cells reactive with mycobacterial hsp65 can cross react with human hsp60
ie. measles virus P3 and MBP

46
Q

Mechanisms of autoimmune disease induction: inappropriate expression of class II MHC

A

Presentation of autoantigens to T helper cells by cells that normally not express class II MHC
Assuming costimulatory signal is also present
IFNgamma production due to trama or viral infection may promote upregulation of class II MHC
IFNgamma induces IL1 expression, which can provide costimulatory signal
ie. pancreatic beta cells from individuals with diabetes have high levels of MHC I/II

47
Q

Mechanisms of autoimmune disease induction: polyclonal B cell activation

A

Lipopolysaccharide from gram negative bacteria and Epstein Barr virus are polyclonal activators or B cells
Do not require presence of T helper cells to cause B cell activation
Activated B cells will synthesize autoantibodies

48
Q

Treatment of autoimmune disease (7)

A
  1. Plasmapheresis
  2. Immunesuppressive drugs
  3. Neutralizing antibodies
  4. Oral administration of potential autoantigens
  5. Peptide blockade of TCR
  6. Administrating monoclonal antibodies
  7. Targeted immunotherapy
49
Q

Treatment of autoimmune disease: plasmapheresis

A

Remove autoantibodies and immune complexes from plasma
Provides temporary relief from symptoms of auto-antibody-mediated autoimmune diseases (ie. rheumatoid arthritis, Grave’s disease)

50
Q

Treatment of autoimmune disease: immunosuppressive drugs

A

Can reduce severity of T cell mediated autoimmune disease
Leave patients are greater risk for infection of cancer
ie. cyclosporin A, FK506

51
Q

Treatment of autoimmune disease: neutralizing antibodies

A

Target molecules invovled in chronic inflammation
ie. TNF-alpha, adhesion molecules
Reduce symptoms of some autoimmune diseases

52
Q

Treatment of autoimmune disease: oral administration of potential autoantigens

A

Can induce tolerance in animal models

Possibly by induction of Treg cells that produce immunosuppressive cytokines (transforming growth factor-beta)

53
Q

Treatment of autoimmune disease: peptide blockade of TCR

A

Of TCR that recognize self-antigen/class II MHC complexes

54
Q

Treatment of autoimmune disease: administration of monoclonal antibodies

A

Target activated autoreactive T cells

ie. antibodies against the CD25 subunit of the high affinity IL2 receptor

55
Q

Treatment of autoimmune disease: targeted immunotherapy

A

Vaccinating with autoreactive T helper cells that have the potential to suppress the activity of autoreactive T cells that cause autoimmune diease which not affecting T cells with other antigen specificities

Immunology 3115 (14 decks)

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