immunotoxicology Flashcards
Overview of innate and adaptive immunity
Innate immunity includes anatomical barriers.
Includes neutrophils, macrophages, mast cells, and eosinophils.
Enzymes complement activation of the innate immune system.
Adaptive immunity is activated by the innate immune sytem. Includes B-lymphocytes which are antigen-presenting and then produce antibodies (humoral). B-cells act as part of immune memory. T-cells (antigen sensing) and natural killer cells destroy infected and diseased cells (cellular immunity). The T-cells induce apoptosis in target cells. T-helper cells (CD4) produce cytokines. T-memory cells are immune memory.
Neutrophils role
Phagocytose microorganisms.
Respiratory bursts to attack pathogens, where they cause ROS, release myeloperoxidase and stimulate hypochlorite generation
Basophils and eosinophils roles
Basophils are basic. they release 5-HT histamine, and heparin. mast cells are basophils.
Mast cells are associated with allergy and anaphylaxis. cause pain, vasodilation, bronchoconstriction. found in connective tissue and mucous membranes
Eosinophils are acidic granules that contain peroxidase, lipase, and ribonuclease. cytokine production (IL-1, TNF-a)
macrophages role
long lived phagocytic cells.
resident macrophages are found in certain organs, e.g., hepatic kupffer cells, CNS microglia, osteoclasts in bone, and dendritic/langerhans in skin.
Can take M1 (inflammatory) or M2 (anti-inflammatory) roles.
M1 produce nitric oxide, H2O2, hypochlorite, and IL-1,-6 and TNFa
M2 assist in tissue healing and release IL-4,-10,-13
The enzyme complement system overview and roles
it is a cascade of 20 enzymes that enhances the ability of antibodies and phagocytic cells. They promote inflammation.
Ways drugs can be toxic when interacting with the immune system
Through:
Immunosuppression
Augmentation of toxic effects in different organs
Hypersensitivity
autoimmunity
These normally occur when the immune system reacts to modified proteins, reactive metabolites, RNA/DNA from bacteria/viruses, mitochondrial DNA, cancer, etc…
Ways to detect modified immune function
Looking at changes to the blood cell counts. Done by looking at surface markers. can also look at cytokine levels.
Looking at risk of cancer and infections.
Asthma
Contact dermatitis
Organ failure
anaphylactic shock.
Animal models are of limited value.
What are haptens and how do they form
A small molecule that binds to a carrier protein, causing it to be identified as non-self by the immune system. occurs by electrophile binding to -SH or lysine residues in the protein.
Animal and in vitro models of immunity
local lymph node assay to identify skin sensitisers. Test the lymph nodes for T-cell proliferation following chemical application.
Reporter antigen popliteal lymph node assay (RA-PLNA) looks at sensitisers induced lymphocyte proliferation. identifies potential for autoimmune or hypersensitivity response
In vitro T-cell activation assays have been used to identify immunosuppressants.
In vitro can also predict hapten formation (direct peptide reactivity assay)
Human modular immune in vitro construct (MIMIC) is used for testing vaccine formulations
Immunosuppressants examples mechanisms of action
corticosteroids suppress hypersensitivity by direct action on T-cells. Cortisol inhibits TNFa but unregulates anti-inflammatory cytokines.
Cyclosporin decreases inflammatory cytokine production (T-cells)
Cyclophosphamide, methotrexate suppress bone marrow.
TCDD inhibits CD-4 development
organotins induce thyme atrophy, and thus reduce T-cell numbers.
Aflatoxins inhibit NK, T-, and B-cell proliferation
Arsenic suppresses T and B cell proliferation and macrophage maturation.
Lead and mercury are autoimmune and lead promotes T2 macrophages. mercury and cadmium inhibit antibody synthesis.
Nitrogen mustards and organophosphates reduce lymphocytes
Types of hypersensitivity and pseudo allergy overview
Type 1:
immediate severe reaction that can cause anaphylaxis or asthma, vasodilation. mediated by IgE degranulation of mast cells - histamine and try-take release.
Seen with penicillin and beta-lactam hypersensitivity.
Pseudo allergy is when chemicals release histamine from mast cells and basophils, but it is not immune mediated, e.g., gaseous anaesthetics, opioids, atropine
Type 2 involves complement activation and phagocytosis. it is involved in organ dysfunction and inflammation.
Type 3 is antigen-antibody complexes alongside complement activation
Type 4 is exemplified by contact dermatitis. Delayed reaction. T-cell mediated. no antibodies.
Drug induced autoimmunity examples
asbestos
Penicillin can cause autoimmune haemolytic anaemia
recombinant cytokines often cause autoimmune responses.
Sulphadiazine can cause systemic lupus erythematous
Other examples of immune responses to drugs and toxins
Tienillic acid
Metamizole
Carbamazepine
Procainamide
Gold thiomalate
Practolol
Halothane
Dihydralazine
P-Aminobenzoic acid derivatives, (hair dyes etc)
