AUTOIMMUNE DISEASES and ENDOGENOUS TOXINS

1
AUTOIMMUNE DISEASES andENDOGENOUS TOXINS

• Alex Lee
• Yuan Zhou
• Jackie Chong
• Luis Chu

2
What Youll Learn

• Autoimmune Diseases
• Focused on Rheumatoid Arthritis
• Endogenous Toxins

3
Endogenous Toxins

• Compounds/metabolites naturally produced in the
  body
• Improper regulation can lead to pathogenesis
• Ex. Excess bilirubin during hemolytic anemia
  (Kernicterus)

4
Immunological Tolerance

• Not attacking and accepting self cells
• Mechanism mostly by clonal deletion and
  clonal suppression where during the
  hemopoietic stem cell maturation process,
  lymphocytes that have receptors for self antigens
  are deleted/suppressed
• The ones that survive this process will
  recognize/attack
• pathogens with foreign antigens only
• Regulated by suppressor T-cells

5
T-cells (Positive and Negative Selection)

• During the T-cell maturation process,
  approximately 98 of the thymocytes die
• Thymocytes are produced in the bone marrow
  without the CD4 or CD8 receptor complex, (these
  complexes are expressed when the thymocytes
  mature in the thymus)
• First Part Positive selection, T-cells that do
  not bind to class I or class II MHC molecules
  will undergo apoptosis and die
• Second Part Negative selection, T-cells that
  have high affinity to the MHC complex of antigen
  presenting cells in the thymus undergo apoptosis,
  or they will be suppressed (This leads to self
  tolerance)
• Similar selection process occurs for B-cells,
  those who produce antibodies that bind strongly
  with self-antigens are inhibited

6
Autoimmunity

• Loss of immunological tolerance/ Failure to
  suppress in the selection process will lead to
  autoimmunity, the lymphocytes will attack the
  specific body cell/tissue that expresses the
  unique self-antigen
• Random/variable parts of T-cell and B-cell
  receptor allow some of these lymphocytes to
  recognize self
• Damage to tissue is caused by immune system,
  including antibodies produced by B-cells,
  cytotoxic T-cells, complement, macrophages
  causing tissue damage and inflammation (harm may
  be directed to single organ or at a systemic
  level depending on the disease)
• Determinant spreading when tissue/cells are
  destroyed, they release a lot of antigens into
  the bodys circulation that are not normally
  present inducing autoimmunity (so activation on
  a specific autoimmune T-cell can induce other
  autoimmune cells ex. A specific autoimmune
  B-cell)
• Molecular Mimicry pathogen antigen causes an
  immune response that cross react with self (ex.
  Streptococcus pyogenes infection ? rheumatic
  fever because the antibodies created are binding
  to the heart short term effect only shigella,
  salmonella, Yersina, camplyobactor infection ?
  reactive arthritis)

7
(No Transcript)
8
O organ-specific, S systemic
This chart is taken from http//microvet.arizona
.edu/Courses/MIC419/Tutorials/autoimmunity.html
9
Risk factors

• HLA (major class of histocompatibility antigens
  in humans) genes usually a specific class I or
  II HLA allele
• Hypothesis 1 HLA allele that are better at
  presenting pathogen peptides similar the to self.
  (ex. HLA B27 class I allele, might bind self
  peptide in absence of tapasin (during an
  infection, tapasin is involved in peptide
  loading), may induce autoimmunity this allele
  is associated with an 80 fold increase risk of
  ankylosing spondylitis)
• Hypothesis 2 HLA allele that are less capable at
  presenting pathogen peptides similar to self
  peptide. (ex. HLA DR3, DR4 and HLA DQ beta which
  are associated with type I diabetes)
• Regular HLA DQ beta has a aspartic acid 57, but a
  mutation to valine, serline, alanine - unable to
  form usually salt bridge ? class II molecule
  instability, altered binding affinity
• Hypothesis these mutation affect negative
  selection of pancreatic islet beta-cell specifc
  T-cell ? increase risk of diabetes
• Identical twins 20 concordance of autoimmune
  disease showing that genes are not the only
  determining factor
• Sex difference (ex. Womens risk of MS or SLE is
  approx. 10-20x greater than men, which mens risk
  of ankylosing spondylitis is 3x than women)
• Associated with infections (hypothesis induce
  inflammatory response that stimulate APC that may
  activate specific autoimmune T cells)

10
Types of Damage

• By antibodies (possible to id antigen) ? type II
  pr type III hypersensitivity
• Antibodies can bind to RBC and initiate
  complement system ? cell lysis opsinization
  (increase phagocytosis)
• Antibodies can bind to cell-membrane
  receptors(ex. May bind to TSH receptor in
  thyroid ? overproduction of thyroid hormone)
• Antibodies can bind to the basement membranes
  type IV collagen(of liver, of kidney)
• IgG production for many self-antigens ? binding
  all overall the body and activating the
  complement system (ex. Systemic lupus
  erythematosis)
• Prolong infection ? continuous production of
  antibodies at a specific site can lead to type
  III sensitivity ? tissue damage
• By T-cells
• Ex. In rheumatoid arthritis, insulin-dependent
  diabetes
• Release of lymphokines
• Pore formation on target cells membrane by
  perforins

11
RHEUMATOID ARTHRITIS

• Diagnosis
• 1. Morning stiffness gt1hr
• 2. Arthritis/Inflammation in gt3 joints including
  1 in the hand
• 3. Symmetric
• 4. Subcutaneous nodules present
• 5. Rheumatoid Factor
• 6. Joint erosion

12
Signs and Symptoms

• Vary from person to person, but patients are more
  likely to be female
• Can start in any joint but usually starts in the
  smaller ones  fingers, hands, wrists
• Joint involvement is usually symmetrical (ex.
  Left right hands)
• More joint erosion the more severe the disease
• Symptoms may come and go, but it is a LIFETIME
  disease
• Flares of disease activity followed by remission
  (cycles)
• Fatigue
• Stiffness of joints esp. in the morning
• Usually, the longer the morning stiffness the
  more severe the disease
• Weakness
• Flu-like symptoms
• Low-grade fever
• Pain from pro-longed sitting
• Muscle pain
• Loss of appetite, depression, anemia, weight
  loss, cold/sweaty hands feet
• Decreased production of tears and saliva
• Rheumatoid nodules underneath the skin usually
  at elbows
• Indicates more severe disease
• Damage to cartilage, tendons, ligaments, and bone

13
(No Transcript)
14
Stages of Progression

• 3 Stages of Progression
• 1st swelling of the synovial lining
• Pain, warmth, stiffness, redness, swelling around
  the joint
• 2nd rapid division and growth of the synovial
  cells
• Synovium thickens (ie. Pannus formation)
• 3rd inflamed cells release enzymes which may
  digest bone and cartilage
• Joint loses shape and alignment
• Pain and loss of movement

15
(No Transcript)
16
(No Transcript)
17
Etiology

• Unknown
• Many theories  genes, environment, hormones are
  all contributory factors
• Genetics
• People with the genetic marker HLA-DR4 at
  increased risk of getting RA

18
cy
19
(No Transcript)
20
Relevance to Pharmacy

• RA is a chronic disease and patients benefit from
  long-term treatment
• There are both drug and non-drug options to this
  common medical condition that pharmacists should
  be aware of
• No treatment provides a cure (yet)

21
Pharmaceutical Options

• Biologics (lowers immune systems ability to
  fight infections)    - Enbrel        -tumor
  necrosis factor (TNF) blocker    - Abatacept
  (Orencia)        - costimulation modulator
• Non-Steroidal Anti-Inflammatory Drugs
  (NSAIDS)    - i.e. Ibuprofen, Indomethacin,
  Ketoprofen
• Corticosteroids    - Prednisone
• Disease-Modifying Anti-Rheumatic Drugs
  (DMARDs)    - more potent, usually in addition
  to NSAIDs    - actually helps slow down the
  destruction of joints    - i.e. methotrexate,
  azathioprine, gold

22
Non-Drug Options

• Regular exercise
• Diet including
• 1) Omega-3 Fatty Acids strong evidence of
  efficacy, decreases production of inflammatory
  chemicals
• 2) Gamma-linolenic Acid need further studies
• 3) Boswellia in an Indian tree blocks
  inflammation
• 4) Devil's Claw (secondary root) works as well
  as Vioxx? - active ingredient hypothesized to
  be iridoid glycosides called harpagosides

23
References

• 1) Janet M. Decker. Autoimmunity Immunology.
  Aug 2003. University of Arizona. Available at
  http//microvet.arizona.edu/Courses/MIC419/Tutoria
  ls/autoimmunity.html      
• 2) Dr Abdul Ghaffar. Tolerance and Autoimmunity
  Microbiology and Immunology Online.2004.
  University of South Carolina. Available at
  http//pathmicro.med.sc.edu/ghaffar/tolerance2000.
  htm
• 3) Berg, Jeremy. Stryer, Lubert. Tymoczko, John
  L. Biochemistry 6th edition. New York. W.H.
  Freeman and Company. 2007.
• 4) Raven, Johnson, Losos, Singer. Biology Seventh
  Edition. New York. McGraw-Hill. 2005
• 5) Arthritis Foundation. Rheumatoid Arthritis.
  2007. Accessed February 2008. http//www.arthritis
  .org/disease-center.php?disease_id31dfcauses
• Fritsche K. Fatty acids as modulators of the
  immune response. Annu Rev Nutr. 26 (2006) 45-73.
  
• 6) Lee S, Gura KM, Kim S, Arsenault DA, Bistrian
  BR, Puder M. Current clinical applications of
  omega-6 and omega-3 fatty acids. Nutr Clin Pract.
  21.4 (2006) 323-341.
• 7) Remans PH, Sont JK, Wagenaar LW,
  Wouters-Wesseling W, Zuijderduin WM, Jongma A,
  Breedveld FC, Van Laar JM. Nutrient
  supplementation with polyunsaturated fatty acids
  and micronutrients in rheumatoid arthritis
  clinical and biochemical effects. Eur J Clin
  Nutr. 58.6 (2004) 839-845.
• 8) Soeken KL, Miller SA, Ernst E. Herbal
  medicines for the treatment of rheumatoid
  arthritis a systematic review. Rheumatology
  (Oxford). 42.5 (2003) 652-659.
• 9) MediResource Inc. Are you getting the RA
  medication that's best for you? C-Health. 2008.
  Accessed February 2008. http//chealth.canoe.ca/ch
  annel_section_details.asp?text_id3304channel_id
  160relation_id16766
• Images Used
• Chronic Inflammatory Pain Control With Omega-5etm
  . Alphaflex. Sierra Life Sciences INC. 2007.
  Accessed February 2008. http//www.alphaflex.com/r
  esearch.html
• Rheumatoid Arthritis. Altmed. Creighton
  University Medical Centre. 2005.
• Accessed February 2008 http//altmed.creighton.ed
  u/FishOil/rheumatoidoverview.htm
• Rheumatoid Arthritis. Medical Look. Accessed
  February 2008. http//www.medicalook.com/Joint_pai
  n/Rheumatoid_arthritis.html
• Rheumatoid Arthritis. Orthopod. 2003. Accessed
  February 2008. http//www.eorthopod.com/public/pat
  ient_education/6596/rheumatoid_arthritis.html

24
Summary

• Autoimmune diseases are caused by a failure of
  the immune system to recognize self from non-self
• Self antigens are mistaken for foreign and the
  immune system attacks self through the release of
  cytokines, antibodies and by cytotoxic cells
  leading to tissue damage (organ specific or
  systemic)
• Rheumatoid Arthritis etiology unknown
• Tumour Necrosis Factor (TNF) induces apoptosis of
  cells resulting in cartilage and bone damage in
  RA Interleukin 1 (IL 1) are also released during
  the immune response
• Risk factors for RA include genetics,
  environment, hormones
• Pharmaceuticals Biologics (ENBREL, Abatacept),
  NSAIDS, Corticosteroids, DMARDs (methotrexate,
  azathioprine, gold)
• Non-pharmaceuticals Exercise, Diet (Omega-3
  Fatty Acids, Gamma-linolenic Acid, Boswellia,
  Devil's Claw)