Week 9 Immunology (2) PDF

AUTOIMMUNITY & IMMUNOMODULATION WEEK 9 ANN DONACHEY [email protected] 1-613-868-2284  SIGN IN FOR EACH SESSION YES, EVEN IF YOU’RE WATCHING THE RECORDING OR JUST DOING THE PRACTICE PROBS  autoimmunity spontaneous, chronic, progress...

AUTOIMMUNITY & IMMUNOMODULATION WEEK 9 ANN DONACHEY [email protected] 1-613-868-2284  SIGN IN FOR EACH SESSION YES, EVEN IF YOU’RE WATCHING THE RECORDING OR JUST DOING THE PRACTICE PROBS  autoimmunity spontaneous, chronic, progressive and self-perpetuating rarely have obvious predispositions, but linked to hormonal and genetic factors immune reactivity involving humoral or cell mediated response lack of induction or maintenance of tolerance can be systemic or organ specific attack against the SELF  predispostions genetic deletion or over-expression of some genes contribute to autoimmunity usually those are MHC genes in humans almost all of them are MHC related Selective breeding for rare dog breedings has predisposed autoimmune susceptibility Diabetes mellitus linked with mutations in DLA-A3, 7, & 10 and B4 breed aggressive phenotype selection causes deleterous autosomal recessive genes to be expressed & loss of MHC polymorphism autoimmunity normal (misdirected) response option 1- cryptic antigens hidden antigens are exposed (cryptic antigens) non-tolerant T cells meet hidden self-antigens and therefore never got that first exposure and therefore the T cells aren’t “trained” to know these hidden antigens are actually the self Examples: ie. blood-testes barrier breaks: releases otherwise hidden antigens into the bloodstream encounter antigen-sensitive cells stimulate autoimmunity ie. heart attack: lysis of cardiac muscle cells expose their mitochondria T cells are like WTF is that, and attack the heart muscle ie. bacterial induced damage to tissues can cause autoantibodies against normal tissue antigens that just shouldn’t be in serum hepatitis causes liver membrane protein autoantibodies normal (misdirected) response option 2- molecular changes normal proteins can develop new epitopes rheumatoid factor (next page) immunoconglutinins autoantibodies directed against complement C2, C4 and C3, upon their activation basically, they get a hair cut and the immune cells are like: I have literally never seen that protein before in my life.  rheumatoid factor Rheumatoid factor are antibodies against other immunoglobulins the antibody’s antibody when Ig binds an antigen, its configuration is altered which displays new antigens this stimulates antibodies (RF) against the antibody rheumatoid factor produced only in diseased states like lupus or arthritis normal (misdirected) response option 3- receptor editing Recall: B cells can undergo central and peripheral tolerance, but this is not a perfect system Receptor edition should manage immature B cells that are self-reactive Mature B cells that recognize the self undergo apoptosis Principle causes: genetic condition: MHC genes strongly associate with autoimmunity abnormally display self antigens inflammation causes localized auto-immune reaction normally hidden antigens are exposed during tissue damage lymphocytes are not tolerant to hidden antigens, only those presented on surface of thymus and therefore induce antibodies to hidden-self- antigens ex: damage to testes barrier causes lymphocyte to produce antigens against sperm, because these are proteins foreign to the rest of the body ex2: myocardial infarction damages heart and can lead to antibody formation against heart muscle mitochondria normal response cross-reacts to a self-antigen when exposed to an actual pathogen physiological aging RBC shed CD47, causing phagocytosis normal (misdirected) response Option 4- molecular mimicry antigen on pathogen shared with an antigen from the host infectious agent leads to an immune response, but it eliminates the pathogen and the very similar looking self-antigens Occurs only when B cells have T cell help ex: Trypanosoma cruzi causes cross reaction to heart and neurons (Chagas disease)  molecular mimicry In B cells, sometimes the self antigen is bound at the same time as the foreign antigen, creating antibodies against both the foreign antigen and the self-antigen that was associated ex: Mycoplasma in swine and cattle cross react with lung antigen Lepto cross reacts with eye antigens causing recurrent uveitis Lyme cross reacts with LFA-1 (leukocyte extravasation) Abnormal immune response Abnormal immune response lack of regulatory mechanisms neoplasma of thymus= reactive T cell production defective AIRE gene associated with: myasthenia gravis (thymic carcinoma linked) rheumatoid arthritis 4x more likely in malignant lymphoid tumor patients defect in Fas/FasL mechanism= no apoptosis mutation encoding apoptotic mechanism mean T cell can recognize but cannot actually cause immune response ie. firing blanks as the bad guy escapes Infection induced autoimmunity reovirus & coxsackie B can lead to production of antibodies against nucleic acid and red blood cells viruses infections have molecular mimicry or cause by-stander effect extra nerd stuff: bystander effect: antigens induce immune reaction of naive cells BUT also cause the release of cells (because of cytokine cascades) that have not been selectively activated by a DC and are therefore non-specific Streptococcus pyogenes can trigger autoimmune response to the heart Lepto cross reacts with eye antigens causing recurrent uveitis Lyme cross reacts with LFA-1 (leukocyte extravasation) causing arthritis autoimmune disorders  autoimmune vaccine reactions Influenza vaccine- Guillain Barre syndrome in humans Rabies vaccine- Anti-thyroglobulin antibodies in beagles (hypothyroidism) Vaccination- immune mediated hemolytic anemia in puppies ADJUVANTS trigger development of low level antibodies sometimes  autoinflammatory diseases extensive and uncontrolled inflammation innate autoimmune initiated examples include: lupus erytematous sjorgen‘s syndrome polyarthritis immune vasculitis endocrine specific autoimmunity Autoimmune Lymphocytitic Thyroiditis- TYPE 2 hypersensitivity dogs (young Dobermans) and chickens antibodies against thyroid peroxidase or thyroglobulin, block T4 and T3 release hypothyroidism obesity hair loss hyperpigmentation pyoderma thyroid tissue infiltrated with lymphocytes causing tissue damage easily missed because clinical signs not apparent until thyroid gland is 75% destroyed biopsy thyroid to determine if lymphocytes have infiltrated ELISA (not effective) treat with levothyroxine (fake T4) to maintain hormone levels Insulin dependent diabetes (type 1 diabetes) mellitus dogs (and rarely cattle) antibodies against islets (beta cells) of pancreas lymphocyte infiltration of pancreas NK cell damages tissue via ADCC hyperthyroidism, lymphocytic parathyroiditis, lyphocytic pancreatitis, adrenalitis Nerve specific autoimmunity Equine Polyneuritis horses adenovirus type 1 infection induced antibodies against myelin of sacral and coccygeal nerves causes tail paralysis Myasthenia gravis dogs ( hereditary in Jack Russel, Fox terriers, sheepdog, labs, dashunds) and cats (Abyssinian) antibodies against acetylcholine receptors at neuromuscular junction of skeletal muscle (and in chronic forms, also titin and ryanodine receptors) antibodies block Ach signal= weak muscles, exercise fatigue rapidly Necrotizing meningoencephalitis, degenerative myelopathy, cerebellar degeneration Eye specific autoimmunity Equinie Recurrent Uveitis recurrent retinitis, uveitis and vasculitis= EYE disease that can lead to blindness antibodies against retinoid and protein S Th1 cell deposits fibrin and collagen clinical signs: lacrimation, photophobia and blepharism viral molecular mimicry plays a role (Borrelia burgdorferii and Onchocerca) Uveodermatological syndromes Uveitis, retinitis and skin depigmentation (whitening of coat) Lymphocytes infiltrate uveal tract Macrophages eat melanin which can detach retina and cause blindness Immune mediated keratoconjunctivitis skin specific autoimmunity Antibodies against hair follicles= hypotrichosis alopecia areata: symmetrical loss of coat in dogs, cats, horses, and cattle antibody against trichohyaline protein in follicle Antibodies against kertinocytes= pemphigus Pemphigus vulgaris: antibody against desmoglein 3 adhesion molecule dogs, cats, horses activates proto-oncogene c-myc causing hyperproliferation of kertinocytes leading to skin separation and bullous (blister) formation disease of dermis (middle layer sloughing) Pemphigus foliaceus: antibody against desmoglein 1 adehsion molecule dogs, cats, goats and horses on squamous cell desmosomes disease of epidermis (top layer sloughing) Bollus pemphigoid: antibody against collagen 17 and laminin 5 (parts of the basement membrane) dobermanns and collies disease of basal membrane (deepest layer sloughing) Which of the following is not true regarding autoimmune disease? a) involves humoral and cell mediated responses b) is acute and progressive c) can be genetically linked and can also be physiological d) involves a lack of tolerance Which of the following is not true regarding autoimmune disease? a) involves humoral and cell mediated responses b) is acute and progressive c) can be genetically linked and can also be physiological d) involves a lack of tolerance Patients with Trypanosoma cruzi infections sometimes have to deal with antibodies against the parasite attacking myocardial cells. This is an example of? a) molecular mimicry b) bystander effect c) type 1 hypersensitivity d) abnormal display of self-antigens Patients with Trypanosoma cruzi infections sometimes have to deal with antibodies against the parasite attacking myocardial cells. This is an example of? a) molecular mimicry b) bystander effect c) type 1 hypersensitivity d) abnormal display of self-antigens A cryptic epitope is which of the following: a. bacterial epitope looks like a part of the host and induces molecular mimicry b. is a part of the host that the immune system was never previously exposed to c. will induce rheumatoid arthritis d. loss of tolerance to a previously known self- antigen A cryptic epitope is which of the following: a. bacterial epitope looks like a part of the host and induces molecular mimicry b. is a part of the host that the immune system was never previously exposed to c. will induce rheumatoid arthritis d. loss of tolerance to a previously known self- antigen A young dobermann patient has arrived displaying signs of obesity, hair loss and hyperpigmentation. You suspect an autoimmune disorder, which of the following is likely false? a) the dog will have high T4 hormone in its serum b) the dog has autoimmune lymphocytic thyroiditis c) the thyroid is being attacked by antibodies d) a thyroid sample will show high lymphocyte infiltration A young dobermann patient has arrived displaying signs of obesity, hair loss and hyperpigmentation. You suspect an autoimmune disorder, which of the following is likely false? a) the dog will have high T4 hormone in its serum b) the dog has autoimmune lymphocytic thyroiditis c) the thyroid is being attacked by antibodies d) a thyroid sample will show high lymphocyte infiltration Alopecia areata is an autoimmune disease associated with: a) hypotrichosis b) pemphigus c) desmoglein d) molecular mimicry Alopecia areata is an autoimmune disease associated with: a) hypotrichosis b) pemphigus c) desmoglein d) molecular mimicry Which of the following is associated with antibody destruction of collagen and laminin? a) bollous pemphigoid b) desmoglein 1 c) uveodermatological syndrome d) recurrent uveitis Which of the following is associated with antibody destruction of collagen and laminin? a) bollous pemphigoid b) desmoglein 1 c) uveodermatological syndrome d) recurrent uveitis immunomodulation  non-specific immunosuppression cytotoxic drugs radiation: alkylating agent: Cyclophosphamide stops cell devision cross links DNA to prevent division also causes collateral DNA damage toxic to resting and dividing cells- especially corticosteroids: immunocompetent cells stimulates IkBa (which inhibits NF-kB) to block impairs T and B cell responses cytokine synthesis risk of bone marrow suppression (leukopenia, both an anti-inflammatory and thrombocytopenia and anemia) immunosuppressive response folic acid antagonist: methotrexate blocks tetrahydrofolate needed to make thymidine and purine nucleotides for DNA synthesis treats rheumatoid arthritis and chemotherapy for cancer DNA synthesis inhibitors: azatiophrine suppress lymphocyte acitvation and mitosis inhibits DNA and RNA synthesis anti-inflammatory activity toxic effect on bone marrow, pancreas and GIT  selective immunosuppression calcinurin inhibitors cyclosporine complexes with cyclophilin blocks calcineurin inhibits signal transduction and blocks IL-2 and IFN-y by T cells blocks Th1 and thereby indirectly suppresses macrophages, B cells, NK cells, neutrophils, eosinophils and mast cells tracrolimmus complexes with immunophilin blocks calcineurin inhibits IL-3, IL-3, IL-4, IL-5 and IFN-y and TNF-a more potent than cyclosporin in inhibiting T and B cell responses Rapamycin complex with immunophilin blocks mTOR (mechanistic Target of Rampamycin) mTOR plays role in regulating T cell activation by integrating all the signals, co-stimulatory signals, cytokines etc and directs the differentiation of T cells into effector, regulatory or memory cells JAK inhibitors JAK-STAT signalling plays a role in immunity, cell division, and cell death- there are a ton and they do many jobs Oclacitinib (apoquel) inhibits JAK 1 involved in itch treats atopic dermatitis blocks JAK1 dependent cytokines IL-2, IL-4, IL-6, IL-13 and IL-31  immune stimulating Bacterial products: source of PAMPs, TLR stimulation and cytokine synthesis Complex carbohydrates: activates macrophages Vitamins: A, D and E Cytokines: IL-2 and recombinants interferons alpha and gamma  trained immunity bacterial product is Bacille Calmette-Guerin (BCG) vaccine for mycobacterial bovis it enhances production of pro-inflammatory cytokines like IL-1b and TNFa and IL_6 effects is that vaccinated individuals have accompanying transcriptional, epigenetic and metabolic reprogramming of myeloid cells so they are more equipped to deal with other viruses Carrot is all grown up, but now we have to treat him for cancer. You only have access to a limited supply of treatment options, which are a variety of non-specific immunosuppressors. Which of the following is true about your options? a) among them are some calcineurin inhibitors to choose from b) radiation stimulates IkBa to have anti-inflammatory and immunosuppressive functions c) a folic acid antagonist is a strong option, because it blocks tetrahydrofolate d) DNA synthesis inhibitors have no toxic effects, so it’s your best option. Carrot is all grown up, but now we have to treat him for cancer. You only have access to a limited supply of treatment options, which are a variety of non-specific immunosuppressors. Which of the following is true about your options? a) among them are some calcineurin inhibitors to choose from b) radiation stimulates IkBa to have anti-inflammatory and immunosuppressive functions c) a folic acid antagonist is a strong option, because it blocks tetrahydrofolate d) DNA synthesis inhibitors have no toxic effects, so it’s your best option. A patient has been vaccinated. This has impacted their immune cells, giving them enhanced ability against viruses unrelated to the vaccine. This is an example of: a) tolerance b) cross-binding c) trained immunity d) selective immunosuppression A patient has been vaccinated. This has impacted their immune cells, giving them enhanced ability against viruses unrelated to the vaccine. This is an example of: a) tolerance b) cross-binding c) trained immunity d) selective immunosuppression THANK YOU