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Transcript of Fadie Jebrail: [email protected]
Fadie Jebrail: [email protected] Taub: [email protected] Gerges: [email protected] Androu Arsanious: [email protected]
March 2nd 2010
PHM 226, 2010Instructor: Dr. Jeffrey Henderson
Autoimmune Disease is a…
“multi-factorial processes involving dysregulation of multiple components of the immune system including the adaptive and the innate immune system” [1]
- Lang et al. Journal of Autoimmunity 2007
Let’s talk about why it’s important first…
Affects 5-8% of people, making it 3rd most common disease after CV disease and cancer
Rarely do people have a SINGLE autoimmune diagnosis, usually associated with chronic disease
Over 80 diseases are characterized as autoimmune disorders
Results from a failure of organism to recognize its own parts as self
This results in overactive immune response directed against body tissue
A bit of immunology..
Two branches: innate/ nonspecific and adaptive/specific
In the innate system: mast cells, neutrophils and macrophages (engulf cytokines inflammation)
Within adaptive, two branches: humoral-mediated (B cells) and cell-mediated (T cells)
Macrophages have a role in both branches
When a pathogen (can be self in this case) is ingested by a macrophage, pathogen proteins attach it to class II MHC
Macrophage activated to deliver signals to T-cells which produces autocrines and stimulate their own production
Helper T cells activate B cells which produce antibodies that inhibit the pathogens
White blood cells within tissue, having a role in innate and adaptive immunity
They engulf pathogens and debris via phagocytosis, and move around via amoeboid movement
Results from a loss of immunological tolerance – which is the ability to ignore self-antigens
T and B lymphocytes that recognize self-antigens are usually destroyed in the Thymus and Bone marrow, respectively, preventing autoimmunity.
Infection and overstimulation of APCs can break tolerance and induce priming of T-cells
A combination of genetics and environment are responsible for autoimmune disease
Human Lymphocyte Antigen (HLA/MHC) is the best predictor as it enhances antigen presentation resulting in increased T-cell activation
Hormones: More common in women; hormones interact with immune cells, especially steroid hormones which influence antibody production
Diet: Iodine binds to thyroglobulin making it a target for the immune system
Drugs: Hydralazine can induce autoantibodies
Antibody-mediated (B cells) Binding of antigens on
the surfaces of B-cells produces antibodies
Autoantibodies: Bind to self-tissue, and
activates the complement cascade which targets the self-antigen to be phagocytosed (opsonized) by Macrophages
Cell-mediated (T cells)• Immune cells both kill
cells directly and indirectly via cytokines (PG, NO, etc.)
• Macrophages: – INITIATE the response
as antigen presenting cells
– PARTAKE in killing cells through antibody dependent-dependent cell-mediated cytotoxicity and by releasing cytokines (TNF and IL-1)
– PRESENT SELF-TISSUE TO T CELLS
Immunosuppressants and anti-inflammatories
B cell depleting agents like rituximab
Anti-cytokine therapies like tocilizumab
No truly effective therapies exist
Autoimmune disease is generally poorly understood
Many different mechanisms exist to ensure that T cells that recognize self are destroyed
Macrophages play a role in both innate and adaptive immunity via complement in the former and antigen presentation in the latter
Know slide 14 Know slide 7
1) Rose, NR. Pathogenic Mechanisms in Autoimmune disease. Clinical Immunology and Immunopathology 53, S7-S16 1989
2) Nauta et al. A regulatory role for Complement in Innate Immunity and Autoimmunity. International Archives of Allergy and Immunology. August 2004. 134, 4 pg 310
3) Fairweather, D. Alternatively Activated Macrophages in infection and autoimmunity. Journal of Autoimmunity 33(2009) 222-230
4) Allman D, Srivastava B, Lindsley RC (February 2004). "Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells". Immunol. Rev. 197: 147–60.
5) http://bioweb.wku.edu/courses/biol328/Lecture11.html6) Ohashi, P. T cell signalling and autoimmunity:
molecular mechanisms of disease. Nature Reviews Immunology Vol. 2 (2002)