Immunodeficiency Week 10 Flashcards

Question

Diagnoses of Primary (congenital) immunodeficiencies in Primary T cell immunodeficiencies are made by what? (2 things)

Answer 1

reduced numbers of peripheral blood T cells, low proliferative responses of blood lymphocytes to polyclonal T cell activators

Answer 2

defects in lymphocyte development or activation defects in the effector mechanisms of innate and adaptive immunity

Answer 3

Defects in NK Cells and Phagocytes -

Answer 4

Inherited disease of Hereford, Japanese Black, and Brangus cattle; mink, persian cats, white tigers, humans, etc. it is a RARE AUTOSOMAL RECESSIVE DISORDER which results in recurrent infections by pyogenic bacT, albinism, excessive bleeding etc. mutation in the lysosomal trafficking regulator (LYST) Neutrophils, monocytes, lymphocytes-->GIANT LYSOMES-->rupture-->tissue damage CD8 t cells and NK cells CANNOT EXCREETE THEIR GRANZYME-RICH GRANULES PARIENTS WILL BE MORE SUSEPTIBLE TO RESPITORY INFECTIONS AND TUMORS

Answer 5

Random gen of AG binding receptors --> makes lymphocytes capable of binding and responding to self-AG. Autoimmune DZ-->develop spontaneously. 2 major catagories include : *Normal IR to Unusual AG *Abnormal IR to normal AG

Answer 6

Hormonal influences and Genetic predisposition

Answer 7

Previously hidden antigens and Molecular Mimicry

Answer 8

failure of regulatory control

Answer 9

Tissue Damage-->intracellular molecules Molecular structural alterations Newly-synthesized antigens

Answer 10

Microbial cross-reactions

Answer 11

Failure to apoptosis virus infections microchimerism

Answer 12

IR to an AG that has been previously hidden (ex:sperm) OR a result of cross reactivity between an infectious agent and a normal body component

Answer 13

to allow for homeostasis and regulation (IgM/IgG) AB against protein fragments or proteins that are damaged due to oxidation (ROS) **Keep in mind some autoimmune responses have a physiological function**

Answer 14

-Nontolerant T Cells meet previously hidden autoAG --T cells are only tolerant if they are first exposed to these AutoAG (AIRE GENE!!) --Ex: testes injury-->may allow for the proteins to reach the BS-->then come in contact with AG-sensitive cells -->autoimmune response --EX: heart attack-->AutoAB will be produced against the mitochondria of the myocardiocytes

Answer 15

can be triggered by the development of completely new epitopes on normal proteins. POP QUIZ: what is an epitope? A: the specific target against which an individual antibody binds. When an antibody binds to a protein, it isn't binding to the entire full-length protein. it is binding to a segment of the protein known as an epitope. Another word for epitope is antigenic determinant--part of the antigen that is recognized by the immune system, specifically by antibodies, b cells or t cells, EX. Rheumatoid factors (RFs) and immunocongluttins (IK)

Answer 16

Produced when large amounts of immune complexes are generated-->autoimmune dz --Rheumatoid arthritis, systemic lupus erythematosus

Answer 17

occurs whenever these factors =activated

Answer 18

REMEMBER B AND T CELLS ARE SPECIAL AND UNDERGO RANDOM GENE REARRANGEMENT. *Do NK cells do this too? y/n As a result autoreactive AG receptors can be created :( Immature B cell-->produces a receptor that binds to selfAG-->B cell will fail to continue to develop-->light chain receptor will undergo recombination-->no longer self reactive. **REMEMBER B CELLS GET A 2 CHANCE This does not occur in mature B cells-->these cells -->apoptosis

Answer 19

Sharing of epitopes between an infectious AG and an autoAG Bcell-->binds to foreign AG and can cross react w/autoAG **THIS REQUIRES T HELPER CELLS Ex. T.cruzi and mammalian neurons and cardiac muscle CDa/18 shares an AG determinant w/ (see diagram in notes)

Answer 20

Hidden epitopes, sustained response is necessary for Dz to develope through Autoimmune dz and lymphoid tumors -Myasthenia gravis-->thymic carcinoma

Answer 21

NZB mice-->persistent infection with a type of c retrovirus-->production of autoAB against nucleic acids and RBC Strep, Pyogenes, lyme dz, lepto may also trigger autoimmune heart dz, arthritis, uveitis

Answer 22

During pregnancy-->mothers and fetuses exchange cells-->fetal cells can persist in the moms body for years-->moms cells are in offspring Y chromosomal DNA has been detected in Golden Retrievers suggesting persistent fetal microchimerism

Answer 23

rabies vax of beagle pups--> increased risk of antithyroglobulin AB 6 mo later Vax--> autoimmune hemolytic anemia vax w/potent adjuvants-->low levels of autoAB Genetic Predisposing factors: -MHC-->are the most NB genes that influence naturally occurring autoimmune dz *Inc restricted MHC polymorphism-->inc autoimmune sus *Diabetes mellitus associated w/DLA-A3,A7,A10 and DLA-B4

Answer 24

Extensive and uncontrolled inflammation caused by innate autoimmunity. -Systemic lupus erythematosus -Discoid lupus erythematosus -Sjorgens syndrome -Autoimmune polyarthritis _immune vasculitis

Answer 25

-lymphocytic thyroiditis -hyperthyroidism -lymphocytic parathyroiditis -autoimmune diabetes mellitus -atrophic lymphocytic pancreatitis -autoimmune adrenalitis

Answer 26

-equine polyneuritis -canine polyneuritis -necrotizing meningoencephalitis -degenerative myelopathy -cerebellar degeneration

Answer 27

-Equine recurrent uveitis -Uveodermatological syndrome -Immune-mediated ketatoconjunctivitis

Answer 28

-Alopecia areata -Pemphigus vulgaris -Pemphigus foliaceus -Bullous pemphigoid

Answer 29

Reproductive Nephritis blood diseases muscle diseases

Answer 30

autograft isograft allograft xenograft

Answer 31

-from the same individual -does not trigger immune response

Answer 32

-from an identical twin -does not trigger immune response

Answer 33

-from a genetically different individual of the same species -different MHC and Blood group -STRONG REJECTION -most frequent type of graft -typically rejects in 1-2 weeks

Answer 34

-from a different species *biochemical and immunological rejection -is rapid and intense within hours

Answer 35

generally never

Answer 36

not reject

Answer 37

will be rejected

Answer 38

genetic defects that result in an increase susceptibility to infection *think YOUNG (usually) monogentetic disease caused by germline mutations--> reg the development/function of the IS autosomonal recessive inheritance (both parents must have the allele) some primary deficiencies are associated with autosomonal dominent inheritance (only need 1 copy of the mutation causes: repeat infections DX: easy, measure serum lg levels, flow cytometry of immune cells or assessment of the neutrophil function Primary t cell def: reduced numbers of peripheral blood t cells and low prolif response can result in defects in: -lymphocyte development -lymphocyte activation -effector mechs of innate or the adaptive IS

Answer 39

not inherited disease but develop as a consequence of malnutrition, cancer, tx w/immunosuppressive drugs, infection **results in an increased susceptibility to infection

Answer 40

results in infection by encapsulated pus-forming bacT and viruses

Answer 41

results in infection by viruses and other intracellular microbes

Answer 42

Inherited disorder in humans, arabian horses, DSH, cocker spaniels and foxhounds failure to granulocyte nuclei to segment not very clinically important other than may be missed DX as inflammation

Answer 43

LAD 1: loss of funcion on the gene encoding for the bets 2 integrin (irish setters) _THIS IS CLAD -What is so important about integrins? LAD2: defect in fucose metabolism that results in a deficiency in the carb structure-->neutrophils cant roll LAD 3: defects in teh activation of beta integrins due to a mutation in the kindlin 3 gene CLAD: LAD1--> result of affected in the integrin mac 1 -Neutrophils cant respond to chemo attractants-->increased risk of infection even with a high number of neutrophils -patient typically dies young due to recurrent bacT infections

Answer 44

* LAD-I – described in Holstein calves – autosomal recessive disease – recurrent bacterial infections, anorexia, gingivitis, periodontitis, chronic pneumonia, and delayed wound healing * Calves die 2-7 months of age; survivors grow slowly and may develop amyloidosis * Large number of intravascular neutrophils but very few extravascular – even in the presence of bacteria * Because T cells also express CD 18, BLAD calves show poor delayed hypersensitivity responses. Neutrophils show reduced responsiveness to chemotactic stimuli and diminished superoxide production and myeloperoxidase activity * BLAD – point mutation in the CD 18 gene – aspartic acid is replaced by glycine – CD 18 is not produced – neutrophils cannot attach to the vascular endothelial cells or emigrate from blood vessels

Answer 45

* Autosomal recessive disease of Border Collies – diluted skin pigmentation, eye lesions, and fluctuation in leucocyte number * Hair – silver grey and the nose is grey – diagnostic feature * Loss of neutrophils – every 11 to 12 days and lasts 3 days * Followed by normal or elevated neutropil count – 7 days * Dogs – severe enteric and respiratory – rarely live beyond 3 y * Puppies – weak, grow poorly, wounds that fail to heal and increased mortality

Answer 46

* Both cell- and antibody-mediated resonses are defective – genetic lesion at the point prior to thymic and bursal cell processing stem cell lesion * Defect in thymic development failure to mount cell-mediated immune responses – normal Ab * Lesion in the B cell – impaired antibody responses Severe Combined Immunodeficiency (SCID) * Foals fail to produce functional T or B cells and have very few circulating lymphocytes * Suckle successfully – aquire maternal Ig * Born healthy – begin to siken by 2 months of age – all die 4 to 6 months – overwhelming infection * Bronchopneumonia – equine adenovirus, Rhodococcus equi, and Pneumocystis

Answer 47

* Primary agammaglobilinemia is rare in foals – animals have no B cells and very low serum Ig * Lymphoid tissues have no primary follicles, germinal centers or plasma cells * Foals – recurrent bacterial infections but may susvive for up to 18 months * Develop septicemia or recurrent respiratory tract infections (Klebsiella pneumoniae and R. equi) * Most foals – Arabian – genetic basis

Answer 48

* Late onset B-cell lymphopenia as a result of impaired B cell production in the bone marrow * Horses where four genes – E2A, PAX5, CD19, and IGD have significantly reduced expression * Resemble primary immunodeficiencies but usually occur in animals over 3 years of age * Recurrent infections not responsive to medical treatment – bacterial meningitis * Serum – only trace levels of IgG, IgM and very low IgA; normal T cell number but undetectable B cells * Necropsy – no B cells in lymphoid organs, blood or bone marrow

Answer 49

* B cell immunodeficiency and profound anemia, hematocrit and B cell numbers decline over 4-12 w * Animals lack germinal centers and plasma cells – Fell and dales ponies * The B cell numbers declines to les than 10% of normal and serum Ig levels drop – maternal Ab catabolization * Severe respiratory disease – opportunistic – adenivirus plus severe diarrhea – Cryptosporidium * Foals die or are euthanized by 1 to 3 months of age * Autosomal recessive disease – mutation in a gene coding for sodium/myoinositol co-transporter

Answer 50

* Angus calf – normal when born – suckeled normally – 6 weekes – pneumonia and diarrhea * Lymphopenic and severely hypogammaglobulinemic (undetectable IgM and IgA and low IgG) * The animal died within a week with systemic candidiasis – syndrome closely resembles equine SCID Selective IgG2 Deficiency Hereditary Parakeratosis * Black Pied Danish and Fresian cattle – born healthy – few weeks – exanthema, hair loss and parakeratosis

Answer 51

* Inbred Yorksire pigs – normal while suckling but gradually overcome by opportunistic infections * Reduced growth, skin lesions and respiratory distress – not survive beyond 60 days * Thymus not visible, lymph nodes were small; B and T cells lacked in the bloodstream but had normal number of NK cells and neutrophils – no antibody response to viral infections * Two spontaneous mutations in the Artemis gene (H12 and H16)

Answer 52

* Jack Russel terriers – SCID phenotype – lymphopenia, agamaglobulinemia, thymic and lymphoid aplasia * Autosomal recessive condition – point mutation stop codon formation and premature termination of the peptide chain * X-linked SCID – Basset Hounds and Corgi – stunted growth, susceptibility to infections and absence of lymph nodes * Born normal – 6-8 weeks develop pyoderma, otitis – pneumonia, enteritis or sepsis – 4 months * X-linked – breeding of a carrier female to a nomal sire – half the males in each litter affected and all females – phenotipically normal

Answer 53

* Selective IgM deficiency – Doberman Pinschers – high IgA, low IgG and very low IgM * Selective immunodeficiencies of IgA – mostly in German Sheperds and Shar-Peis – deficiencies in mucosal immunity * Cavalier King Charles Spaniels with Pneumocystis pneumonia had reduced IgG levels compared to normal dogs

Answer 54

* Family of inbred Weimaraners – immunodeficiency and dwarfism * Normal at birth – at 6-7 weeks developed a wasting syndrome – emaciation and letargy * Thymuses – atrophied and lacked a cortex; normal Ig levels, Th cells activity unimpared * Growth hormone treatment caused thymic cortical regeneration and clinical improvement * Disease – due to a deficiency of growth hormone as a result of a lesion in the hypothalamus – the thymus requires growth hormone to function

Answer 55

* Deficiencies of the immune system often develop because of abnormalities that are not genetic but acquired during life * Acquired immunodeficiency diseases are, in fact, more common than congenital immunodeficiencies and are caused by a variety of pathogenic mechanisms * Disorders in which immunodeficiency is a frequent complicating element include malnutrition, cancer, and infections * Viruses that invade the immune system are – affect primary lymphoid tissues * affect secondary lymphoid tissues * Chickens – infectious bursal disease virus (IBDV) destroys lymphocytes in the bursa of Fabricius * IBDV is not completely specific for bursal cells; it also destroys cells in the spleen and thymus

Answer 56

Loss of lymphocytes – common in virus infections since viral survival and persistence may require immunosupression

Answer 57

Lymphopenia – in feline panleukopenia, canine parvovirus-2, feline leukemia ans African Swine Fever

Answer 58

Bovine viral diarrhea virus (BVDV) causes destruction of both T and B cells

Answer 59

Equine herpesvirus-1 causes a drop in T-cell numbers and depresses cell-mediated responses in foals

Answer 60

Bovine herpesvirus-1 (BHV-1) also causes a drop in T cells and depresses macrophage cytotoxicity and IL-1 synthesis

Answer 61

Alveolar macs and causes enzootic pneumonia

Answer 62

Porcine Reproductive Respiratory Syndrome (PRRS) – destruction of alveolar macrophages – severe enzootic pneumonia

Answer 63

* Virus that destroys secondary lymphoid organs – predilection for lymphocytes - lymphopenia * Major cellular receptor is CD150 – expressed on activated B and T cells * tonsils – bronchial lymph nodes to the blood stream – kills T and B cells * Invades the thymus, spleen, lymph nodes – destroys more cells – thymic atrophy, depleted lymphocytes in spleen and tonsils * CD4+, CD8+ and CD21+ B cells – most affected * Supresses production of IL-1 and IL-2, IL-12 and B-cell maturation * Immunosupresion – clinical disease – dogs develop Pneumocystis pneumonia – supressed animals * Also causes demyelinating leukoencephalomyelitis; demielinization is enhanced by Cytotoxic CD8+

Answer 64

* More than 40 lentiviruses – isolated from nunhuman primates – simian immunodeficiency viruses (SIV) selectively invades CD4+ T cells * The viruses stimulate a strong but ineffective immune response- immunodeficiency syndrome similar to AIDS in humans – are believed to be transmitted sexually * Clinical progression is slow - animals develop lymphadenopathy, severe wheight loss, severe chronic diarrhea, lymphomas and opportumictic – Pneumocystis, Mycobacterium, Candida and Cryptosporidium * Macaques are depleted of CD4+ T cells, macrophages and dendritic cells * Two cellualar receptors – CD4 and CCR5 * 25% of infected do not mount an immune response and die 3-5 m severe encephalitis; the rest mount immune response – 1-3 y after. No spontaneous recovery

Answer 65

* More common than the lentiviruses – transmitted by biting – broader tropism than SIVs – in addition to macrophages and lymphocytes can also infect fibroblasts, epithelial cells, and the brain * Profound drop in serum IgG and IgM and severe lymphopenia * Generalized lymphadenopathy, hepatomegaly, and splenomegaly * Loss of lymphocytes from the T-dependent areas of the secondary lymphoid organs * Similar changes to AIDS in humans * Opportunistic agents such as Pneumocystis, cytomegalovirus, C. parvum or C. albicans cause infection * Some monkeys develop tumors – fibrosarcomas * Half develop neutralizing antibodies and survive, the other die – septicemia or diarrhea with wasting *transmitted via biting, affects macs, lymphocytes, fibroblasts, epi cells and the brain. *50% survival rate

Answer 66

* Oncogenic retrovirus with a unique surface protein – feline oncornavirus cell membrane antigen (FOCMA) – expressed on FeLV-infected cells * On exposure to FeLV, about 70% of cats become infected, but the remaining 30% do not * Of the infected cats, 60% become immune and 40% become viremic * Of the viremic, 10% cure spontaneously and 90% remain infected for life * Initial transient viremia and spread in lymphoid organs – lymphopenia and neutropenia 1-2 weeks after infection * FeLV causes multiple cancers – lymphosarcomas, reticulum cell sarcomas, erythroleukemias and granulocytic leukemias

Answer 67

* Bacterial infections – Mannheimia hemolytica, the actinobacilli, and some streptococci * Parasitic infectations – Toxoplasma or trypanosomes, Trichinella spiralis, and Demodex * Toxin-induced immunosuppresion – polychlorinated biphenyls, iodine, lead, cadmium, DDT * -mycotoxins – Fusarium; aflatoxins – Aspergillus * Malnutrition, obesity, trace elements, vitamins

Answer 68

Innate or adaptive

Answer 69

-surgical trauma and ischemia --increase MHC expression --DAMPS --Cytokines and inflammatory mediators TLR MICA (stress) can activate NK cells

Answer 70

Direct: donor APCs mismatch with recipient T cells-->recognition of foreign material Acute rejection indirect: recipient APC mismatch-->recipient T cells Chronic rejection Associated with minor antigenic differences

Answer 71

1- CD8+ T cells destroy vascular endothelium to graft via caspase-mediate apoptosis *Hemorrhage-->PLT aggregation-->thrombosis-->stoppage of blood flow 2. CD4+ T cells release TNF alpha--> apoptosis in endothelial cells 3. Activated Macrophages: pro-inflammatory cytokines impair graft function and intensify T cell-mediated rejection

Answer 72

1- Hyperacute- 48 hours after graft 2-accellerated- up to 7 days after graft 3- Acute -after 7 days **all of these are acute b/c they use the same mechanism! 4-Chronic- several months after graft

Answer 73

Several antigens: -blood group glycoproteins-->easier to match -MHC molecules -polymorphism: individuals differ in the MHC haplotype -Endogenous antigens presented on the MHC 1 -Antibodies and T cells participate in the rejection

Answer 74

1- rare 2-associated with pre-existing Abs that bind to donor endothelial Ags 3-Thrombotic occlusion of the graft vasculature 4-minues to hours after host-grafted blood vessels are anastomosed -can be seen with imcompataible blood

Answer 75

1- refers to both accelerated and acute rejection 2. Injury to graft mediated by alloreactive T Cells and Abs 3-inflammation=result of T cells releasing pro-inflammatory cytokines 4-Alloantibodies bind to donor endothelial antigens and cause damage 5-incomparable MHC molecules 6-a repeated graft from the same donor will involve antibodies and the complements and results in RAPID graft rejection 7-CS: Acute kidney rejection-->rapid rise in creatinine, enlarged kidney, depression, vomiting, hematuria and proteinuria

Answer 76

-not much to do with MHC 2-arterial occlusion occurs due to proliferation of intimal smooth muscle cells 3-graft eventually fails doe to ischemic damage 4-associated with chronic inflammation 5-slowly activates immune response 6-CS: rejection of kidney, rejection creatinine and urea levels rise gradually, proteinuria

Answer 77

Balance between immunosuppression to prevent rejection and not making animal more susceptible to other infection: 1- inhibit t cell signaling pathway 2-antimetabolites-metabolic toxin to kill t cell 3-function blocking or depleting anti-lymphocytic antibodies 4-co-stimulatory blockage-drugs that block t cell co stimulatory pathways 5-targeting alloantibodies and alloreactive b cells 6-anti-inflamatory-->corticosteroids

Answer 78

-Rejection in 6-14 days if untreated -unrelated dogs with renal allografts need simultaneous bone marrow allografts from the donor animal -median survival time is 8 months

Answer 79

-without immunosuppression die in 8-34 days -59-70% 6 mo survival -40-50%-3 year survival

Answer 80

Require Total Body irradiation or chemotherapy -space for growing transplanted cells -reduce intensity of rejection -in leukemia pets--> destroys tumor

Answer 81

Caused by reaction of grafted mature T cells in bone marrow with allo-antigens of the host -remember that recipient has been immunocompromised to get this transplant and now cannot reject grafted cells Acute: epithelial death in the skil, liver, GI tract--> rash jaundice, diarrhea, GI hemorrhage Chronic: fibrosis and atrophy of one or more same organs.