Autoimmunity & Immunodeficiency Week 9 PDF

AUTOIMMUNITY & IMMUNODEFICIENCY 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 predispositi...

AUTOIMMUNITY & IMMUNODEFICIENCY 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 genetic predispostions 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 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 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 Microchimerism =low level of cells from a genetically distinct individual that are haboured in the self differs from a graft, where whole tissues would be transplanted mothers can keep cells from their fetuses, fetuses can keep cells from their mothers Microchimeric cells can cause autoimmune disorder if we do not become tolerant 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 selfantigen 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 selfantigen IMMUNODEFICIENCY ANN DONACHEY [email protected] WHATSAPP: 1-613-868-2284 IMMUNODEFICIENCY Failure of the innate, humoral, or cell-mediated limbs of immunity primary immunodeficiency: defect of T or B lymphocytes genetic: developmental defects can occur at any stage of development secondary immunodeficiency: defect that ultimately results in a loss of antibody or lymphocyte function later in life can be caused by cancer, malnutrition, drugs or infection outcome= increased susceptibility to infection humoral deficiency= bacterial window of opportunity cellular deficiency= viral/ intracellular microbe window of opportunity PRIMARY IMMUNODEFICIENCY Caused by germline mutations that mess with development higher risk in consanguineous (inbred) families where same mutation is being inherited, but possible in nonconsanguineous families When its possible: Chronic or recurring infections in young animals multiple sites of infection atypical infections failure to respond to antibiotics or chemo lack of vaccine response leukocytosis or leukocytopenia Diagnosis: measure serum Ig levels flow cytometry of immune cells evaluate cell levels/ functions PRIMARY IMMUNITY Chediak-Higashi Syndrome Pelger-Huet Anomaly Canine Leukocyte Adhesion Deficiency (CLAD) Bovine Leukocyte Adhesion (BLAD) Canine Cyclic Neutropenia (CCN) Severe Combined Immunideficiency Disease (SCID) X-linked (X-SCID) Selective Deficiencies Common Variable Immunodeficiency (CVID) PRIMARY IMMUNITY CHEDIAK-HIGASHI SYNDROME SPECIES persion cats CAUSE missense mutation in lyst gene Hereford and Japanese black autosomal & Brangus cattle recessive horses mink white tigers orcas MECHANISM mutated lysosomal membrane trafficking formation of a large lysosomes granules can fuse and rupture (neuts, eosinos, monocytes and melanocytes) causing tissue damage and induce early release of NK cell ganules leukocytes reduced chemotactic activity & cytotoxicity CLINICAL SIGNS melanocyte defect: loss of skin colour and hair pigment eye abnormalities neut/mono/NK/T cell defect: increase risk to infection higher risk of tumors septicemia (pyogenic bact) endothelial defect: hematoma (injection site bruises) hemorrahge PRIMARY IMMUNITY PELGER-HUET SYNDROME SPECIES arabian horses DSH cats cocker spaniels foxhounds CAUSE inherited disorder MECHANISM failure of segmentation of granulocyte nuclei look like a permanently immature stage, but are otherwise functionally normal CLINICAL SIGNS animals are fine incidental finding PRIMARY IMMUNITY CANINE LEUKOCYTE ADHESION DEFICIENCY (CLAD) TYPE 1 SPECIES Irish Red or White Setters CAUSE lack of integrin (Mac-1) CD11b/CD18 mutation in beta chain of CD18 (integrin B-2) LAD-2: metabolic defect causes def. in sialyl lewis X = no rolling LAD-3: mutation of kindlin-3 gene= no activation MECHANISM no chemotaxis for neutrophils no extravasation out of blood vessels cannot ingest c3b opsonized particles extreme leukocytosis, neutrophillia and eosinophilia CLINICAL SIGNS die of severe infections recurrent infections lymphadenopathy delayed wound healing DX blood pannel PRIMARY IMMUNITY BOVINE LEUKOCYTE ADHESION DEFICIENCY (BLAD) SPECIES Holstein calves CAUSE lack of integrin (Mac-1) CD11b/CD18 autosomal recessive, point mutation in beta chain of CD18 (integrin B-2) asp replcaced with glycine MECHANISM no chemotaxis for neutrophils no extravasation out of blood vessels extreme leukocytosis, neutrophilia and eosinophilia no delayed hypersensitivity response CLINICAL SIGNS die BETWEEN 2-7 months old of severe infections cause stunted growth and develop amyloidosis large number of neutrophils in blood but not in tissues DX blood pannel PRIMARY IMMUNITY CANINE CYCLIC NEUTROPENIA GREY COLLIE SYNDROME SPECIES border collies appears after weaning, die before they’re 3 years CAUSE Autosomal recessive MECHANISM cyclical arrests of maturation of myeloid progenitor cells loss: every 11-12 days, lasts for 3 days, levels out over 7 days neutrophils have reduced myeloperoxidase activity CLINICAL SIGNS DX recurrent bacterial and coat!! fungal infections discolouration of hair & nose treat bleeding symptoms GI, resp, bone diseases PRIMARY IMMUNITY SEVERE COMBINED IMMUNODEFICIENCY DISEASE (SCID) SPECIES Arabians (horses) Jack Russels (dogs) born healthy problems at 2 months of age (protected by colostrum) die by 4-6 months Angus, Black Pied Danish and freisan cattle CAUSE Autosomal recessive MECHANISM do not produce functional T or B cells do not recognize antigens no germinal center in spleen or lymph node no antibodies CLINICAL SIGNS underdeveloped or no thymus may have functional innate cells agammaglobulinemia severe bacterial infections get brutal bronchopneumonias DX NEED these 3 factors: few lymphocytes lack of IgM in serum histology (shitty primary and secondary lymphoid organs) PRIMARY IMMUNITY SEVERE COMBINED IMMUNODEFICIENCY DISEASE (SCID) CONTINUED SPECIES CAUSE Inbred Yorkshire Pigs Two spontaneous mutations: Artemis gene H12 and H16 MECHANISM do not produce functional T or B cells do not recognize antigens no germinal center in spleen or lymph node no antibodies CLINICAL SIGNS DX NEED these 3 underdeveloped or no factors: thymus few may have functional lymphocytes innate cells lack of IgM in agammaglobulinemia serum severe bacterial histology (shitty infections primary and get brutal skin lesions, secondary poor growth and lymphoid bronchopneumonias do not live more than 60 organs) days PRIMARY IMMUNITY IMMUNOGLOBULIN DEFICIENCIES SPECIES foals specifically arabians CAUSE no B cells MECHANISM no B cells no primary follicles no germinal centers no plasma cells CLINICAL SIGNS frequent infections usually septicemia or resp infections usually die by 18 months DX PRIMARY IMMUNITY FOAL IMMUNODEFICIENCY SYNDROME SPECIES foals fell and dale ponies CAUSE MECHANISM autosomal recessive disease loss of Na/myosoinositol transporter less than 10% of normal B cell populatioin no primary follicles no germinal centers no plasma cells CLINICAL SIGNS frequent infections usually resp infections usually die by 1-3 months DX PRIMARY IMMUNITY COMMON VARIBALE IMMUNODEFICIENCY CVID SPECIES Horses OLDER THAN 3 years BUT still genetically based CAUSE B cells don’t produce enough Ig because of a lack of CD4 T cell stimulation reduced expression of E2A, PAX5, CD19 and IgD MECHANISM low IgG and IgM, very low igA few B lymphocytes normal T lymphocytes CLINICAL SIGNS frequent infections non-responsive to treatment +/- acute hepatitis DX no B cells in lymphoid organs at necropsy PRIMARY IMMUNITY X-LINKED SEVERE COMBINED IMMUNODEFICIENCY DISEASE (XSCID) SPECIES ONLY MALES basset hounds & corgis appears at 6-8 weeks after colostrum wears off CAUSE Recessive X-linked (half of males in each litter affected) mutation of gamma chain in IL-2 receptor bassets: removal 4 nucleotides--STOP corgis: insertion of cytosine--STOP MECHANISM lack lymph nodes lymphocytes are not reactive to IL-2, so no mature T lymphocytes reduced lymphocytes CD4:CD8 ratio is 15:1 when it should be 2:1 B lymphocytes may be normal- normal IgM level but reduced IgG and IgA because they can’t class switch CLINICAL SIGNS frequent infections tiny thymus w/o cortex bone marrow normal but tiny lymph nodes DX PRIMARY IMMUNITY IMMUNOGLOBULIN DEFICIENCIES SPECIES Cavalier King Charles Spaniels: IgG Dobermanns: IgM German Sheep Dogs and Sharpei: IgA CAUSE Hereditary block in differentiation of B cells into IgA or IgG producing antibodies MECHANISM Number of B cells normal, but defective differntiation PRIMARY IMMUNITY T CELL DEFICIENCY SPECIES weimaraners normal at birth wasting syndrom ~6 weeks CAUSE MECHANISM growth hormone deficiency caused by hypothalamic lesion atrophied thymus w/o cortex T helper cells normal normal Ig levels CLINICAL SIGNS immunodeficiency and DWARFISM DX tx with growth hormone therapy SECONDARY IMMUNITY When its possible: damage to normally functional immune system MORE COMMON infectious agents THAN PRIMARY virus infection that acts on lymphatic organs (primary and secondary) lymphopenia reduction of reactivity hypogammaglobulinemia toxins stress malnutrition cancer old age SECONDARY IMMUNITY CANINE DISTEMPER VIRUS SPECIES canine CAUSE invade and attack T and B lymphocytes MECHANISM virus enters via CD150 receptor leading to activation and uses the cells for replication initially tonsils -> lymph nodes -> blood damages spleen, MALT and thymus causes lymphopenia leading to immunosuppression CLINICAL SIGNS higher susceptibility to infection pneumonia demyelinating leukoencephalomalacia kills CD4, CD8 T cells and B cells DX SECONDARY IMMUNITY FELINE LEUKEMIA VIRUS SPECIES felines CAUSE invade and attack CD4 T lymphocytes has feline oncornavirus cell membrane antigen FOCMA on infected cells MECHANISM virus tropism for lymphoid tissue attacks T cells and reduces their number CLINICAL SIGNS wasting syndrome due to recurrent infections thymus atrophy other lymphoid tissue atrophy immunosuppression multiple cancer types (lymphosarcoma etc) DX SECONDARY IMMUNITY FELINE LEUKEMIA VIRUS EXPOSED CATS 70% INFECTED 40% BECOME VIREMIC 90% INFECTED FOR LIFE 30% FIGHT IT OFF AND ARE FINE 60% DEVELOP IMMUNITY 10% SPONTANEOUSLY CURED SECONDARY IMMUNITY RETROVIRUS SPECIES primates CAUSE lentivirus like human AIDs MECHANISM sexually transmitted slow progression depletion of CD4 T cells, macrophages and DC cells CLINICAL SIGNS lymphadenopathy weight loss chronic diarrhea lymphoma (cancer) opportunistic bacteria 25% do not mount any immune response and die in 3-5 months of encephalitis (brain infection) the rest get responses are recover 1-3 years after DX SECONDARY IMMUNITY TYPE D SIMIAN RETROVIRUS SPECIES primates CAUSE bite transmission slow progression depletion of CD4 T cells, macrophages, fibroblasts, epithelial cells and brain MECHANISM drop in IgG and IgM lymphopenia fibrosarcoma development CLINICAL SIGNS lymphadenopathy hepatomegaly splenomegaly weight loss chronic diarrhea fibrosarcoma (cancer) opportunistic bacteria half survive, rest die of septicemia DX ORGAN GRAFT REJECTION TYPES OF GRAFTS graft: donor cells, tissues, or organs are removed and placed in a recipient host orthotopic: tissues placed in its normal anatomic location ie. kidney transplant heterotopic: tissues placed at a different site transfusion: transfer of circulating blood cells or plasma graft rejection: result of adaptive immune response creates memory, so will have an accelerated rejection if a graft from the same donor is attempted again TYPES OF GRAFTS Autograft: host tissues are moved to a different part of the animal’s own body no immune response triggered Isograft or syngeneic: transplanted between two genetically identical individuals parents can donate to offspring, but offspring cannot donate to parent inbred siblings can donate to each other no immune response Allograft: transplanted between genetically different members of the same species most frequent type- becoming routine for kidneys and bone marrow caused by different MHC and blood type antigens (aka alloantigens) rejection Xenograft: grafts transplanted between species antigens are called xenoantigens causes the strongest immune rejection reaction TYPES OF GRAFTS rejection: non-identical individuals offspring receiving donations from non-inbred parents accepted: genetically identical individuals offspring receiving donations from inbred parents ALLOGRAFT REJECTION major source of foreign molecules: blood groups: trigger antibody formation MHC cl.1 and 2: trigger T cell responses mechanism: infiltration with CD8 cytotoxic T cells, which damage the endothelial cells lining vessels trying to stops blood flow hemorrhage thrombosis death of the graft repeating the graft from the same donor will involve antibodies and complement, so the rejection will occur faster REJECTION PROCESS DIRECT PATHWAY: graft APC (donor DC cell) tries to work with host T cells, and they realize this is a non-self MHC 1 or 2 and causes immune reaction unprocessed INDIRECT PATHWAY: host APC recognizes graft tissue MHC, reports back to a T cell proper processing and presentation like any other foreign antigen recognition ANTIBODIES: donor specific antibodies= antibodies against the grafted antigen from alloreactive B cells recognize MHC 1 and MHC 2 INNATE INPUT: donated tissues temporarily lose blood suppy, causing release of DAMPs (damage associated molecular patterns) DAMPs stimulate innate cells, which can do their own damage and activate adaptive response REJECTION PROCESS hyperacute rejection: minutes to hours after grafting sensitized individuals pre-existing antibodies bind donor cell antigens endothelial damage thrombotic occlusion of blood vessels acute rejection: rejection after 7 days injury to parenchymal cells and blood vessels mediated by T cells and antibodies cytokines produced by helper T cells and CD8 T cells kill parenchymal and endothelial cells triggers complement activation, neutrophilic and NK cell mediated damage chronic rejection: rejection after several months arterial occlusion due to proliferation of intimal smooth muscle cells graft fails due to ischemia eventually seen in kidney, heart, lungs and liver PREVENTION OF ALLOGRAFT REJECTION GOAL: prevent rejection while doing the minimal amount of immunosuppression MATCH: minimize alloantigenic differences by blood grouping and MHC testing GENERAL STRATEGIES: inhibit T cell signalling: cyclosporine prevent excess IL-2 & rapamycin inhibit growth factor mediated T cell proliferation antimetabolites: azathioprine kill proliferating T cells function-blocking or depleting anti-lymphocyte antibodies: antibodies that inhibit T cells costimulatory blockade: drugs that block T cell costimulation (soluble CTLA-4) target alloantibodies and alloreactive B cells anti-inflammatory drugs: corticosteroids but caution, because they increase risk of infections and tumors XENOGENIC TRANSPLANTS cross species humans already get pig heart valves but hyperacute rejection due to natural antibodies is a major issue, just like in allografts can often be more severe form of rejection making genetically modified pigs that have human complement regulatory proteins even still, we are seeing delayed xenografic rejection due to an acute vascular rejection occuring 2-3 days post transplant....basically, we are working on it, but don’t expect cross species transplants to be coming to a clinic near you anytime soon. FETAL AND NEONATAL IMMUNITY IMMUNE SYSTEM DEVELOPMENT PASSIVE TRANSFER: fetuses acquire immunity from their mothers (antibodies and maybe T cells) they develop fully functional adaptive and innate mechanisms over time the longer the neonate gestates, the more developed their immune system is at birth but either way, it takes time for them to have like full, adult level immunity 1. THYMUS 2. SECONDARY LYMPHOID ORGANS 3. B CELLS MADE SOON AFTER WE SEE SPLEEN AND LYMPH NODES 4. ANTIBODIES NOT GENERATED UNTIL LATER IN FETAL LIFE IMMUNE SYSTEM DEVELOPMENT So when are the fetuses actually immunocompetent? neonatal pigs: 90 days post-conception: neutrophils capable of phagocytosing bacteria, but have poor locomotion 75% of pathogen clearance at 100 days post-conception: develop bactericidal activity from blood by liver and spleen after birth: macrophages have depressed chemotactic response few days old: alveolar macrophages finally differentiate by 7 days of age: alveolar macrophages actually have phagocytic potential later in life: virucidal activity and complement opsonization potential gradually By 2 months 75% of acquired (reaches adult levels @ 14 days old) pathogen clearance from lungs INTRAUTERINE INFECTIONS mild maternal infection may be severe or lethal in the fetus BVD is a big deal, and the timing of infection AND strain impacts the outcome CYTOPATHIC STRAIN: 0-100 days: maternal abortion, mumification or resorption of fetus 100-150 days: malformations of the calf (neurological, failure to thrive etc.) 150-200 days: normal calf NON-CYTOPATHIC STRAIN: 50-120 days: carrier of BVD, but asymptomatic due to tolerance 150-200 days: normal calf NOTE: cattle can be born with the non-cytopathic strain, and then become infected with cytopathic BCD after birth, causes mucosal disease PLACENTAL TRANSFER maternal fetal antibody transfer can depend on the Ig being transferred and the placental structure usually anything less than 170 kDa are transferred (mainly IgG) Placental types: Epitheliochorial: equids, pigs, camelids 6 layers of separation thickest non-permeable to antibodies animal DEPENDS on colostrum passive transfer Syndesmochorial: ruminants (cotyledones) 5 layers of separation semi-permeable Endotheliochorial: cats & dogs (carnivores) 4 layers of separation thin (medium permeability) 5-10% permeation of IgG Hemochorial: primates and rodents 3 layers of separation thinnest of them all (most permeable) amazing antibody transfer of IgG only PLACENTAL TRANSFER maternal fetal antibody transfer can depend on the Ig being transferred and the placental structure usually anything less than 170 kDa are transferred (mainly IgG) Placental types: Epitheliochorial: equids, pigs, camelids 6 layers of separation thickest non-permeable to antibodies animal DEPENDS on colostrum passive transfer Syndesmochorial: ruminants (cotyledones) 5 layers of separation semi-permeable Endotheliochorial: cats & dogs (carnivores) 4 layers of separation thin (medium permeability) 5-10% permeation of IgG Hemochorial: primates and rodents 3 layers of separation thinnest of them all (most permeable) amazing antibody transfer of IgG only COLOSTRUM accumulated during the last two weeks of pregnancy triggered by estrogens and progesterones contains IgG mainly (65-90%) , but minorly IgA, IgM and IgE as the animal continues to lactate, colostrum turns into milk dominant immunoglobulin depending on species and liquid type: primates: more IgA in milk and colostrum pigs and horses: IgG in colostrum, but more IgA found in milk ruminants: IgG dominates in milk and colostrum ONLY POSSIBLE IN FIRST 24-36 HOURS OF LIFE: Ig absorbed via pinocytosis in GI tract and transported to basolateral side of cells on an Fc receptor possible, because there is a deficiency of secretory mucosa, so there is less enzyme activity that would normally destroy the proteins reduced protease activity but also colostrm contains trypsin inhibitors FAILURE OF PASSIVE TRANSFER PRODUCTION FAILURE: insufficient, low quality colostrum low immunoglobulins in colostrum and milk low volume of colostrum pre-mature elakage of colostrum pre-mature fetus means not enough colostrum made in time INGESTION FAILURE: poor absorption late administration of colostrum fetal defect inhibits ability to drink poor mothering ABSORPTION FAILURE: calf drinks, but it doesnt get absorbed chemical mediators inhibit absorption damages of intestinal mucosa YOLK IMMUNITY from Hen to Egg protects chicks at hatching birds have IgM, IgA and IgY (IgYolk which is equal to IgG) Order of production based on life stage: IgM- transferred in egg white first transffered IgY- transferred in yolk through selective receptors second transfered about 10-20mg/ml of IgY in yolk proportional to the serum IgY of mom (not according to egg size) amount of IgY in hatched chicks is 2-3mg total (compared to 100-400mg present in yolk) IgA- transferred in egg white last transferred LOCAL, ACQUIRED IMMUNITY intestinal lymphoid tissues respond to ingested antigen piglets vaccinated orally 3 days after birth with TGE develop antibodies in intestine 5-14 days later early resistance can come from innate production of interferon (recall anti-viral cytokines) early intestinal IgM response can isotype switch to IgA by 2 weeks old IgA response is the one that becomes the most robust in the shortest amount of time SYSTEMIC, ACQUIRED IMMUNITY maternal antibodies inhibit the newborn to mount its own response this is why we don’t vaccinate really young animals- there is no B cell response and no B cell memory formed the maternal antibodies just wreck it but T cell response unaffected by maternal antibodies concentration of maternal antibody is a factor and dose of the vaccine also influences this response calves with maternal antibodies don’t make their own until 4 weeks of age this is why we wait until 6-8 weeks of age to start vaccinating puppies and kittens calves that do not receive colostrum can make own antibodies at 1 week of age in orphaned animals, vaccinations at 2 weeks of age is appropriate vaccinate puppies: distemper, adenovirus, parvovirus, lepto and parainfluenza: first vax: 6-8 weeks booster at 8-12 weeks final booster at 12-16 weeks rabies vax @ 16 weeks vaccinate kittens: viral rhinotracheitis, calicivirus, panleukopenia first vax: 6-9 weeks booster at 9-12 weeks final booster at 12-16 weeks leukemia vaccine firsrt @ 9-12 weeks and booster @12-14 weeks rabies vax @ 12 weeks WHICH OF THE FOLLOWING DEFINES IMMUNODEFICIENCY? a) it is a primary or secondary failure of the immune response b) it is only a failure of leukocytes and complement c) primary immunodeficiency occurs from viral infections d) only results from pluripotent stem cell defects WHICH OF THE FOLLOWING DEFINES IMMUNODEFICIENCY? a) it is a primary or secondary failure of the immune response b) it is only a failure of clotting and complement c) primary immunodeficiency occurs from viral infections d) only results from pluripotent stem cell defects WHICH OF THE FOLLOWING IS NOT AN EXAMPLE OF PRIMARY IMMUNODEFICIENCY? a) BLAD b) X-SCID c) FeLV d) Isotype deficiency WHICH OF THE FOLLOWING IS NOT AN EXAMPLE OF PRIMARY IMMUNODEFICIENCY? a) BLAD b) X-SCID c) FeLV d) Isotype deficiency YOU ARE DOING A VISIT FOR A 3 MONTH OLD FOAL WHO PRESENTS WITH PALE SKIN AND HAS DEVELOPED CATARACTS. YOU SUGGEST RUNNING BLOODWORK TO FIGURE OUT WHAT’S GOING, AND NOTE EXCESSIVE BLEEDING AND HEMATOMA FORMATION FROM THE SITE OF THE BLOOD DRAW. WHAT DO YOU SUSPECT IS OCCURING? a) Sever combined immunodeficiency b) Cyclic neutropenia c) Chediak-Higashi Syndrome d) CLAD YOU ARE DOING A VISIT FOR A 3 MONTH OLD FOAL WHO PRESENTS WITH PALE SKIN AND HAS DEVELOPED CATARACTS. YOU SUGGEST RUNNING BLOODWORK TO FIGURE OUT WHAT’S GOING, AND NOTE EXCESSIVE BLEEDING AND HEMATOMA FORMATION FROM THE SITE OF THE BLOOD DRAW. WHAT DO YOU SUSPECT IS OCCURING? a) Sever combined immunodeficiency b) Cyclic neutropenia c) Chediak-Higashi Syndrome d) CLAD YOU’VE GOTTEN THE FOAL’S BLOODWORK BACK AND CAN CONFIRM IT’S CHS. WHAT DID YOU FIND ON THE BLOODWORK THAT CONFIRMS THIS? A) NO DISULFIDE BONDS IN BETA CHAIN B) HIGH LEVELS OF NEUTROPHILS IN THE BLOOD BUT NOT IN TISSUES C) ENLARGED GRANULES INSIDE NEUTROPHILS D) A LACK OF IGM YOU’VE GOTTEN THE FOAL’S BLOODWORK BACK AND CAN CONFIRM IT’S CHS. WHAT DID YOU FIND ON THE BLOODWORK THAT CONFIRMS THIS? A) NO DISULFIDE BONDS IN BETA CHAIN B) HIGH LEVELS OF NEUTROPHILS IN THE BLOOD BUT NOT IN TISSUES C) ENLARGED GRANULES INSIDE NEUTROPHILS D) A LACK OF IGM YOUR FAVOURITE CLIENTS ARE GETTING A NEW PUPPY, BUT THEY’VE HEARD THERE ARE SOME BREED PREDISPOSITIONS THEY SHOULD BE AWARE OF...WHICH OF THE FOLLOWING IS NOT TRUE? a) white setters are prone to canine cyclic neutropenia b) border collies can suffer from canine cyclic neutropenia c) golden retrievers tend to get X-SCID d) Cavalier’s can get IgG deficiencies YOUR FAVOURITE CLIENTS ARE GETTING A NEW PUPPY, BUT THEY’VE HEARD THERE ARE SOME BREED PREDISPOSITIONS THEY SHOULD BE AWARE OF...WHICH OF THE FOLLOWING IS NOT TRUE? a) white setters are prone to canine cyclic neutropenia b) border collies can suffer from canine cyclic neutropenia c) golden retrievers tend to get X-SCID d) Cavalier’s can get IgG deficiencies TRUE OR FALSE SCID prevents TCRs and BCRs from undergoing recombination of the variable region. TRUE OR FALSE SCID prevents TCRs and BCRs from undergoing recombination of the variable region. CANINE DISTEMPER USES WHICH OF THE FOLLOWING RECEPTORS TO INFECT AND REPLICATE IN T CELLS? A) CD47 B) CD150 C) FCER1 D) CD134 CANINE DISTEMPER USES WHICH OF THE FOLLOWING RECEPTORS TO INFECT AND REPLICATE IN T CELLS? A) CD47 B) CD150 C) FCER1 d) CD134 WHICH OF THE FOLLOWING SITUATIONS WOULD RESULT IN A GRAFT REJECTION? a) skin is moved from a patient’s abdomen to heal a burn on their own forelimb b) a kidney is transplanted from a parent to their biological offspring c) a littermate donates skin to their sibling d) an offspring donates a kidney to their parent in renal failure. WHICH OF THE FOLLOWING SITUATIONS WOULD RESULT IN A GRAFT REJECTION? a) skin is moved from a patient’s abdomen to heal a burn on their own forelimb b) a kidney is transplanted from a parent to their biological offspring c) a littermate donates skin to their sibling d) an offspring donates a kidney to their parent in renal failure AFTER COMPLETING AN ALLOGRAFT OF A KIDNEY, YOU ARE DOING A POST OPERATIVE FOLLOW UP AND NOTE THAT THERE IS MACROSCOPIC HEMATURIA AND A SMALL HYPERECHOIC KIDNEY ON ULTRASOUND. WHAT IS OCCURING? A) NORMAL PART OF HEALING B) ACUTE REJECTION C) CHRONIC REJECTION D) ACCELERATED REJECTION AFTER COMPLETING AN ALLOGRAFT OF A KIDNEY, YOU ARE DOING A POST OPERATIVE FOLLOW UP AND NOTE THAT THERE IS MACROSCOPIC HEMATURIA AND A SMALL HYPERECHOIC KIDNEY ON ULTRASOUND. WHAT IS OCCURING? A) NORMAL PART OF HEALING B) ACUTE REJECTION C) CHRONIC REJECTION D) ACCELERATED REJECTION WHICH OF THE FOLLOWING DESCRIBES ACUTE REJECTION OF A GRAFT? A) ANTIBODIES AGAINST ENDOTHELIUM CAUSES A THROMBUS OF ARTERIES B) T CELLS DAMAGE PARENCHYMA CAUSING INFLAMMATION AND DAMAGE TO ARTERIES C) PROLIFERATION OF SMOOTH MUSCLE CAUSES ISCHEMIC DAMAGE TO ARTERIES D) GRAFT IMMUNE CELLS ATTACK HOST ANTIBODIES WHICH OF THE FOLLOWING DESCRIBES ACUTE REJECTION OF A GRAFT? A) ANTIBODIES AGAINST ENDOTHELIUM CAUSES A THROMBUS OF ARTERIES B) T CELLS DAMAGE PARENCHYMA CAUSING INFLAMMATION AND DAMAGE TO ARTERIES C) PROLIFERATION OF SMOOTH MUSCLE CAUSES ISCHEMIC DAMAGE TO ARTERIES D) GRAFT IMMUNE CELLS ATTACK HOST ANTIBODIES AFTER DOING A GRAFT, THE GOAL IS TO USE SOME IMMUNOSUPPRESSANTS TO MINIMIZE RISK OF REJECTION. YOU HAVE A CAT WHO HAS JUST UNDERGONE AN ALLOGRAFT OF BONE MARROW. WHICH OF THE FOLLOWING IS A MEDICATION YOU MIGHT USE POST-OPERATIVELY? a) cyclosporine: will function as a co-stimulatory blockade b) cyclosporine: will inhibit T cell signalling pathways c) azathioprine: antimetabolits kill proliferating B cells d) better to not treat to avoid resistance AFTER DOING A GRAFT, THE GOAL IS TO USE IMMUNOSUPPRESSANTS TO MINIMIZE RISK OF REJECTION. YOU HAVE A CAT WHO HAS JUST UNDERGONE AN ALLOGRAFT OF BONE MARROW. WHICH OF THE FOLLOWING IS A MEDICATION YOU MIGHT USE POST-OPERATIVELY? a) cyclosporine: will function as a co-stimulatory blockade b) cyclosporine: will inhibit T cell signalling pathways c) azathioprine: antimetabolits kill proliferating B cells d) better to not treat to avoid resistance YOU ARE A RESEARCHER ANALYZING ANTIBODIES IN NEWBORNS. YOU SAMPLE BLOOD BEFORE AND AFTER THEY HAVE HAD COLOSTRUM. WHICH OF THE FOLLOWING WOULD BE TRUE? a. you would expect 10% of expected IgG to be present from placental transfer b. cattle samples before colostum would contain high amounts of IgG c. foals would have sufficient IgG due to the highly permeable placenta d. in the calves, IgA will be the highest concentrated antibody after they receive colostrum YOU ARE A RESEARCHER ANALYZING ANTIBODIES IN NEWBORNS. YOU SAMPLE BLOOD BEFORE AND AFTER THEY HAVE HAD COLOSTRUM. WHICH OF THE FOLLOWING WOULD BE TRUE? a. in kittens you would expect 10% of IgG to be present from placental transfer b. cattle samples before colostum would contain high amounts of IgG c. foals would have sufficient IgG due to the highly permeable placenta d. in the calves, IgA will be the highest concentrated antibody after they receive colostrum A BVD infection has been prevalent on a local farm. One cow has had an abortion, and you were able to test the fetus to confirm the diagnosis. You are worried about the rest of the pregnant cows in the herd. Many are at 122 days of gestation. What is your major concern? a. calves will be born tolerant b. mummification c. malformations d. don’t worry, everyone will be normal A BVD infection has been prevalent on a local farm. One cow has had an abortion, and you were able to test the fetus to confirm the diagnosis. You are worried about the rest of the pregnant cows in the herd. Many are at 122 days of gestation. What is your major concern? a. calves will be born tolerant only for non-cytopathic strain, if we have already had an abortion, lets be worried about the cytopathic strain b. mummification only from 0-100days c. malformations from days 100-150 days d. don’t worry, everyone will be normal THANK YOU! GOODLUCK