Review of Autoimmune mechanisms Flashcards
Rheumatoid arthritis
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
What is inflammation?
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
Acute inflammation
caused by initial (innate) immune response
Rubor (redness) Calor (heat) Dolor (pain) Tumor (swelling) Functio Laesa (loss of function)
Vasodilation
Edema
Leukocyte Migration
elements of innate immunity
epithelial barriers phagocytes dendritic cells complement NK cells (0-12 hours)
elements of adaptive immunity
B lymphocytes
T lymphocytes
1-5 days
Chronic Inflammation
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
Cytokines in acute inflammation
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
Cytokines in chronic inflammation
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
Why is the body mountin an immune response to self-antigen?
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
HLA susceptibility
Ankylosing spondylitis- HLA-B27
RA: HLA DRB1, 4, 10
Type 1 diabetes: HLA-DRB1*0301/0401
Pemphigus vulgaris: HLA-DR4
HLA: Human MHC (classes and CD cells)
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)
T Cell Receptors bind…
HLA: peptide
HLA is responsible for presenting self-peptides to
T-cells in the thymus
Molecular mimicry
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
Altered peptides
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
Rheumatoid Arthritis is a Type IV autoimmune disease…
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)
Rheumatoid Arthritis hasType III characteristics
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
Treatment of RA
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
What do monoclonal antibodies used to treat RA actually target?
Why, immune system mediators of course!
CD20
IL-6 receptor
TNF
What do B cells do?
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.
Monoclonal antibodies as treatment for disease
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
What is RA?
anti-immunoglobulin autoantibodies
smoking
increases inflammation
