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Autoimmune Disorders Osama A. Badary, PhD Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Immunity. Innate Immunity. Adaptive Immunity. Barriers (skin) Secretions (lysozyme) Complement Inflammation Granulocytes NK cells Macrophages
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Autoimmune Disorders Osama A. Badary, PhD Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
Immunity Innate Immunity Adaptive Immunity Barriers (skin) Secretions (lysozyme) Complement Inflammation Granulocytes NK cells Macrophages Phagocytosis B cells-- Antibody production T cells-- Cell mediated immunity Immunoregulation
Forms of Immunity • Cell Mediated Immunity • Macrophagesphagocytize pathogens • Upon phagocytosis macrophages present non self antigens on their membranes • Helper T cells recognize non self antigens and recruit cytotoxic T cells • Cytotoxic T cells destroy infected cells • Antibody Mediated Immunity • Helper T cells recognize non self antigens and stimulate B cells to produce antibodies • B cells release antibodies which bind to non self antigens present on infected cells • B cells complete their maturation upon binding to non self antigens and destroying infected cells
The Antibody Response: Secondary Response IgG, IgA, IgE Primary Response T Cell Dependent IgD/IgM t Ag Ag
Self (Immunologically): MHC Class II MHC Class I Antigen Presenting Cell (APC)
MHC Class II + peptide MHC Class I + peptide Antigen Presenting Cell (APC)
CD8 T cell CD4 T cell T cell receptor (TcR) TcR Class II Class I Antigen Presenting Cell (APC)
Autoimmunity: • Immune reactivity against self. • Generally classed into systemic (e.g. SLE, RA,) and organ-specific (e.g. MS, IDDM, AITP etc.). • Affect 5-7% of the population – often with debilitating symptoms
MHCII Macrophage (APC)
1. Phagocytosis MHCII Macrophage (APC)
Destruction 2. 1. Phagocytosis MHCII Macrophage (APC)
Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. 1. Phagocytosis MHCII Macrophage (APC)
Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. Phagocytosis MHCII Macrophage (APC)
Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. Phagocytosis MHCII Peptides 3. Macrophage (APC)
Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. Phagocytosis MHCII Peptides 3. 4. Macrophage (APC) Abnormal Presentation
Infection, Cytokines (e.g. TNF, IFN) APC Activation Destruction 2. Altered processing 1. CD4+ T cell Activation Phagocytosis MHCII TcR Peptides 3. 4. Macrophage (APC) Abnormal Presentation of a platelet autoantigen
Diagnosis: Autoimmune Disease • Genetic predisposition • coding for the variety of MHC molecules • Demographics • most common among middle aged women • Additional viral infections • Disease specific environmental factors • Aging, stress, hormones, pregnancy
Autoimmune Disease • Three types of autoimmune disorders: • Cytotoxic (Type II reactions) • Immune complex (Type III reactions) • Cell-mediated (Type IV reactions)
Autoimmune Diseases A. Type II (Cytotoxic) Autoimmune Reactions Involve antibody reactions to cell surface molecules, without cytotoxic destruction of cells. • Grave’s Disease: • Antibodies attach to receptors on thyroid gland and stimulate production of thyroid hormone. • Symptoms: Goiter (enlarged thyroid) and bulgingeyes. • Myasthenia gravis: • Progressive muscle weakness. Antibodies block acetylcholine receptors at neuromuscular synapse.
Autoimmune Diseases B. Type III (Immune Complex) Autoimmune Reactions • Systemic Lupus Erythematosus • Rheumatoid Arthritis C. Type IV (Cell-Mediated) Autoimmune Reactions Insulin-dependent (Type I or Juvenile) Diabetes Mellitus
Possible Causes: Inefficient lymphocyte programming “Self proteins” circulate without having been exposed to system (ex: sperm, eye lens, thyroid) Reactions between self-antigens and antibody production against foreign antigens Potential Treatments: Control inflammation (ex: diabetes mellitus) Immunosuppressive Medication (ex: corticosteriods, cyclosporin, methotrexate) Therapeutic Antibodies against specific T cell molecules (with fewer side effects) Autoimmune Disease
Blood • Autoimmune Thrombocytopenia (AITP)
Acute: Childhood disorder. Abrupt onset. Usually follows infectious illness. Spontaneous remission. Chronic: > 6 month duration. Organ specific autoimmune disease. Autoantibodies enhance platelet destruction. Presence of GPIIIa-reactive T cells. Cytokine abnormalities. Autoimmune Thrombocytopenia: Platelet count: <150x109/L
Nomenclature difficulties?: ITP: Idiopathic Thrombocytopenic Purpura Immune Thrombocytopenic Purpura ATP: Autoimmune Thrombocytopenic Purpura - (adenosine triphosphate - oops) AITP: AutoImmune Thrombocytopenic Purpura
AITP: Therapy Steroids (1950’s- ) -Antigen- specific therapy Vinca Alk., Danazol Cyclophosphamide (1970’s) -Oral Tolerance Chronic Cyclosporin IFN, VitC etc. (1980’s- ) Anti-CD40L (1998- ) Rituxan (1998- ) Gammaglobulins (1981- ) Anti-D (1984- )
Gastrointestinal Autoimmune Disorders • Crohn’s disease • Ulcerative colitis • Celiac disease
The Gut Lumen • Villi- (singular: villus) are tiny, finger-like structures that protrude from the wall of the intestine -Microvilli- hairlike structure on the surface of absorptive and secretoryepithelial cells • Epithelial Tissue- layer of cells which line the GI tract • Enterocytes – layer between gut lumen and absorptive cells
Inflammation & Damaged enterocytes Helper T cell Plasma cells Antibodies anti-gliadin anti-endomysial And tissue transglutaminase ab T cell receptor HLA-DQ2/DQ8 molecule Lymphocytes (T cells , Natural Killer cells and B cells) Cytokines (Interferon-g, TNF-a, IL-15 etc) Antigen Presenting Cell GUT LUMEN GUT LUMEN Gliadin, GP Enterocytes LAMINA PROPRIA AND INTRA EPITHILIAL SPACE
Deamidated Gliadin • Gliadins are best known for their role, along with glutenin, in the formation of gluten. • Deamidated gliadinis produced by acid or enzymatic treatment of gluten. • The enzyme, tissue transglutaminase, converts some of the abundant glutamines to glutamic acid. • This is done because gliadins are soluble in alcohol and cannot be mixed with other foods (like milk) without changing the foods qualities. • Deamidated gliadin is soluble in water. • The cellular immunity to deamidated α-/β-gliadin is much greater than α/β-gliadin and can result in symptomatic gluten-sensitive enteropathy.
Crohn's disease (ileitis or enteritis) • abdominal pain (lower right area) and diarrhea • Rectal bleeding, weight loss, (bleeding may be serious leading to anemia) • arthritis, skin problems, and fever may also occur. • Children with Crohn’s disease may suffer delayed development and stunted growth
Drug Therapy • Anti-Inflammation Drugs: Sulfasalazine • Cortisone: Prednisolone • Immune suppressor: azathioprine • Infliximab • Surgery
Celiac disease • (gluten-sensitive enteropathy • A digestive disease that damages the small intestine and interferes with absorption of nutrients. • When people with celiac disease eat foods containing gluten, their immune system responds by damaging the small intestine.
gas chronic diarrhea pale, foul-smelling weight loss fatigue unexplained anemia bone or joint pain osteoporosis, osteopenia behavioral changes tingling numbness in the legs (from nerve damage) seizures missed menstrual periods (often because of excessive weight loss) infertility, recurrent miscarriage delayed growth pale mouth sores tooth discoloration or loss of enamel itchy skin rash called dermatitis herpetiformis Symptoms
Complications • Blockage of the intestine. • Sores, or ulcers, • Infected fistulas (surgery) • Nutritional complications
Ulcerative colitis • Ulcerative colitis is an inflammatory bowel disease (IBD). It can be difficult to diagnose because its symptoms are similar to Crohn’s disease. It involves one section of inner lining of the colon starting of the rectum. • Crohn’s disease differs because it causes inflammation deeper within the intestinal wall and can occur in other parts of the digestive system including the small intestine, mouth, esophagus, and stomach