PHM142 Autoimmune Disorders + Idiosyncratic Drug Reactions 1
Autoimmune Disorders Auto-reactivity: low physiological levels (e.g. tolerance) vs. pathogenic levels 80+ types of autoimmune diseases affect approx. 5-9% of the population of the western world Organ-specific (e.g. type 1 diabetes, multiple sclerosis) vs. Systemic (e.g. rheumatoid arthritis, systemic lupus erythematosus) Involve over-activation of innate and adaptive immunity; genetic susceptibility 2
The Inefficiency of Selection Negative selection: mechanism by which autoreactive lymphocytes are eliminated apoptosis or anergy.but it s leaky 3
The Inefficiency of Selection Negative selection: mechanism by which autoreactive lymphocytes are eliminated apoptosis or anergy.but it s leaky 4
Activation of Escaped Autoreactive Cells Deficiency in inhibitory surface molecules Stores of anergic cells Breaches in anatomical barriers (immunoprivelleged sites - e.g. brain, eye, testis) 5
Rheumatoid Arthritis A chronic inflammatory autoimmune disease (joints) Risk factors include: genetics - esp. MHC Class II (shared epitope) sex - women environmental - e.g. smoking, silica, obesity, microbiota diversity, low SES 6
Rheumatoid Arthritis Seropositive Rheumatoid Arthritis: characterized by the presence of autoantibodies 1. anti-igg antibodies (Rheumatoid Factor) 2. anti-citrullinated protein antibodies (ACPAs) Citrullinated proteins play a key role in RA development peptidyl arginine deiminase 7
Rheumatoid Arthritis Citrullinated proteins: bind MHC Class II proteins that contain the shared epitope (AA sequence in +vely charged P4 pocket of peptide binding domain) are expressed on osteoclast cell surface MHC Class II MHC Class II Malmstrom et al. Nature Rev Immunology 2016 8
Rheumatoid Arthritis Smollen et al. Nature Reviews 2018 9
Rheumatoid Arthritis: Treatment Disease-modifying antirheumatic drugs (DMARDs): target inflammation and reduce progression of structural damage Methotrexate - the anchor drug for RA treatment; used in conjunction with glucocorticoids; mechanism of action unknown maybe purine depletion -> DNA replication inhibition -> apoptosis maybe adenosine signaling (inhibits Adenosine deaminase/amp deaminase activity -> increased AMP and adenosine levels -> anti-inflammatory) maybe DNA methylation Non-steroidal anti-inflammatory drugs (NSAIDs) 10
Lupus Systemic lupus erythematosus - characterized by autoantibodies against nuclear antigens Characterized by: rash, oral and nasal ulcers, alopecia, renal issues, neurological symptoms, anemia, thrombocytopenia Increasing incidence and prevalence Genetic, hormonal, and environmental risk factors 11
Lupus + The Complement System C1 deficiencies associated with high prevalence + severe manifestation 1. Herditary C1 deficiency -> Lupus point mutation in A/B/C peptide -> premature stop codon missense mutation -> non-functional protein 2. Lupus -> C1 consumption 3. Lupus -> anti-c1 autoantibodies 12
Lupus, C1 + Apoptosis Apoptosis: a tightly-regulated, non-inflammatory, cellautonomous, form of cell death involving controlled DNA fragmentation, apoptotic body formation, and subsequent phagocytic engulfement (phosphotidylserine) Apoptotic body clearance is abnormal in patients with lupus Autoimmunity due to C1 deficiency may be due to impaired disposal of dying cells and immune complexes 13
Lupus: Treatment NSAIDs antimalarials (e.g. hydroxychloroquine) corticosteroids (e.g. prednisone, methylprednisone) immunosuppressants (e.g. azathioprine, cyclophosphamide, methotrexate) 14
Idiosyncratic Drug Reactions an adverse reaction that does not occur in most patients treated with a drug and does not involve the therapeutic effect of the drug IDRs are the most common type of adverse drug reaction - unpredictable, often life-threatening thought to be immune-mediated and caused by chemically-reactive species animal models are difficult 15
Characteristics of IDRs major targets: skin, liver, bone marrow (blood cells) each drug has spectrum of IDRs eg halothane IDRs limited to the liver vs carbamazepine IDRs include liver injury, skin rash, agranulocytosis, aplastic anemia, autoimmunity. delayed onset more rapid onset upon second exposure genetic component - MHC genes, slightly higher risk in women 16
IDRs of the Skin 1. Maculopapular Rash most common type of IDR skin rash onset: 1-2 weeks of treatment resolves even with continuation of drug mediated by cytotoxic CD4 cells that bind MHC Class II 17
IDRs of the Skin 2. Urticaria (Hives) second most common type of IDR skin rash IgE-mediated allergic reaction usually responsive to cyclosporine 18
IDRs of the Skin 3. Fixed Drug Eruption rash occurs at the same site (hyperpigmentation) onset is approx. 2 hours upon rechallenge mediated by CD8 T cells 4. Drug-Induced Hypersensitivity Syndrome acute onset of rash, fever and hepatitis/nephritis/pneumonitis/ carditis/thyroiditis/hematologic abnormalities onset is 2-6 weeks; mortality rate up to 10% treatment: corticosteroids 19
IDRs of the Skin 5.Acute Generalized Exanthematous Pustulosis pustules on the face, neck and groin; fever; neutorphilia onset as short as one day largely associated with antibiotics 6. Toxic Epidermal Necrolysis sudden onset of fever and malaise followed by painful rash and blisters - gentle pressure results in sloughing off of the epidermis due to keritinocye apoptosis mortality rate approx 30% - th emost severe type of skin rash involves mucus membranes of the mouth, genitals, intestine, and eyes (sometimes blindness) onset is 7-21 days 20
IDRs of the Liver 1. Hepatocellular Liver Injury most common idiosyncratic liver injury involves death of hepatocytes onset usually 1-3 months; can be days to one year damage is often greater in the regions of the liver containing high levels of cytochrome p450 2. Cholestatic Liver Injury characterized by a greater increase in alkaline phosphotase and bilirubin compared to alanine transaminase associated with phenothiazines, amoxicillin/ clavulanic acid, and flucloxacillin 21
IDRs of the Blood 1. Agranulocytosis peripheral neutrophil count under 500 cells/microliter onset is 1-3 months 2. Thrombocytopenia classically associated with heparin - antibodies to heparin-platelet factor 4 complexes; no memory 3. Anemia due to hemolysis or decreased production of RBCs aplastic anemia: lack of hematopoietic cells in the bone marrow 22
Mechanisms of IDRs The Hapten Hypothesis: chemically reactive drug/ metabolite binds protein -> drug-modified protein adduct recognized as foreign -> results in immune response Hapten (definition): a low molecular weight chemical that binds irreversibly to protein through formation of a covalent bond 23
The Hapten Hypothesis Uetrecht Annu. Rev. Pharmacol. Toxicol. 2007 24
MIDTERM Oct. 19th @ 11:45, EX100 25