Review of Autoimmune mechanisms Flashcards

1
Q

Rheumatoid arthritis

A

Most common of the rheumatic diseases
Affects up to 3% of USA
Women: men, 3:1
Can run in families
Chronic, episodic inflammation of joints
Starts between age 20-40 y/o
80% patients have rheumatoid factor (anti-IgG antibodies) or anti-CCP antibodies
Joints infiltrated with leukocytes and proinflammatory cytokines
Tissue erosion
Treated with NSAIDs, steroids, or monoclonal antibodies that target TNF-alpha or B cells

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2
Q

What is inflammation?

A

a tissue reaction that delivers mediators of host defense to sites of infection and tissue damage”

Mediators: Circulating cells, molecules secreted by cells and molecules derived from plasma proteins

Purpose: Eliminate pathogens, remove dead cells, repair tissue

Bystander effects: Mediators can also damage normal or uninfected tissue

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3
Q

Acute inflammation

A

caused by initial (innate) immune response

Rubor (redness)
Calor (heat)
Dolor (pain)
Tumor (swelling)
Functio Laesa (loss of function)

Vasodilation
Edema
Leukocyte Migration

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4
Q

elements of innate immunity

A
epithelial barriers
phagocytes
dendritic cells
complement
NK cells (0-12 hours)
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5
Q

elements of adaptive immunity

A

B lymphocytes
T lymphocytes

1-5 days

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6
Q

Chronic Inflammation

A

Occurs if can’t eliminate the cause of acute inflammation – constant stimulus
Persistent infection
Self-antigen (the case for RA)
Prolonged exposure to toxic agents

Persistent or episodic inflammation

Mediators:
Cells: T cells, B cells, antibodies, macrophages
Proteins: cytokines, plasma proteins

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7
Q

Cytokines in acute inflammation

A

TNF (from macrophages, mast cells, T-lymphocytes)- stimulates epression of endothelial adhesion molecules and secretion of other cytokines, systemic effects

IL-1 (from macrophages, endothelial cells, some epithelial cells)- similar to TNF; greater role in fever

IL-6 (from macrophages, others)- systemic effects (acute phase response)

Chemokines (from macrophages, endothelial cells, T lymphocytes, mast cells, other cell types)- recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues

IL-17 (from T lymphocytes)- recruitment of neutrophils and monocytes

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8
Q

Cytokines in chronic inflammation

A

IL-12- (from dendritic cells, macrophages)- increased production of IFN-gamma

IFN-gamma (from T lymphocytes, NK cells)- activation of macrophages (increased ability to kill microbes and tumor cells)

IL-17 (fro T lymphocytes) - recruitment of neutrophils and monocytes

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9
Q

Why is the body mountin an immune response to self-antigen?

A

Susceptibility genes –> failure of tolerance, unregulated lymphocyte action

Environmental factors (infection, smoking)–> enzymatic modification (e.g. citrullination) of self protein

These two things combine to cause T and B cell responses to self antigens

–> Fibroblasts, chondrocytes, and synovial cells proliferating and releasting collegenase, stromelysin, elastase, PGE2 and other enzymes

–> Pannus formation, destruction of bone, cartilage, fibrosis, ankylosis

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10
Q

HLA susceptibility

A

Ankylosing spondylitis- HLA-B27

RA: HLA DRB1, 4, 10

Type 1 diabetes: HLA-DRB1*0301/0401

Pemphigus vulgaris: HLA-DR4

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11
Q

HLA: Human MHC (classes and CD cells)

A

Human Leukocyte Antigen

Each individual expresses several different MHC class I and II molecules

The human MHC encodes 
3 class I molecules that bind CD8+ TCR (HLA-A, B, and C)

3 class II molecules that bind CD4+ TCR (HLA-DR, DP and DQ)

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12
Q

T Cell Receptors bind…

A

HLA: peptide

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13
Q

HLA is responsible for presenting self-peptides to

A

T-cells in the thymus

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14
Q

Molecular mimicry

A

Infections are environmental factors that can trigger autoimmune disease
Autoimmunity may be caused by self peptides that mimic pathogen derived peptides and stimulate T-cell response

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15
Q

Altered peptides

A

Cyclic citrullinated peptides (CCPs) are produced during inflammation
T-cells are not tolerized to citrullinated peptides (antigens)
HLA-DRB1*04 is expected to be particularly good at presenting citrullinated peptides to T cells.
Activated T cells can activate B cells specific for the citrullinated antigen
These B cells would make plasma cells that make anti-CCP antibodies

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16
Q

Rheumatoid Arthritis is a Type IV autoimmune disease…

A

Type IV
* Caused by effector T cells
* Delayed reaction! What would be an example of this?
Unknown synovial joint antigen
Antibodies are involved, but not the initial cause
Sensitized Th1 cells release cytokines that activate macrophages or Tc which mediate direct cellular damage

(TB test is another example– takes a few days)

17
Q

Rheumatoid Arthritis hasType III characteristics

A
Type III
Produce autoantibodies (called * rheumatoid factors) that are IgM specific for determinants in the Fc region of IgG.

IgM-IgG immune complexes circulate in the blood and deposit in the joints.

Complement is activated and damage occurs

Ensuing inflammatory response mediated by massive infiltration and exacerbated inflammation

18
Q

Treatment of RA

A

NSAIDs
Steroids

DMARDs (nonspecific):
   MTX
   Sulfasalazine
   Hydroxychloroquine
   Leflunamide - pyrimidine synthesis inhibitor
   Minocycline
Biologic DMARDs (specific):
   TNFi - 
   Abatacept – blocks T cell costimulation
   Rituximab – depletes B cells
   Tocilizumab - blocks IL6 receptor
   Tofacitinib – inhibits Janus Kinase 3
19
Q

What do monoclonal antibodies used to treat RA actually target?

A

Why, immune system mediators of course!

CD20
IL-6 receptor
TNF

20
Q

What do B cells do?

A

Make plasma cells that make antibodies

CD20 is on all B cells; when we target it we kill off all the B cells. That person will make no more antibodies.

21
Q

Monoclonal antibodies as treatment for disease

A

Mouse antibodies can elicit an immune response in humans
Making a chimeric antibody can reduce this - Rituximab (Rutuxin) is a successful chimeric antibody
Humanized antibody - may be even better. Oxalizumab (Xolair) specific for IgE for use in allergic asthma
Human antibody - Adalimumab (Humira) specific for TNF-alpha, treatment for rheumatoid arthritis

22
Q

What is RA?

A

anti-immunoglobulin autoantibodies

23
Q

smoking

A

increases inflammation