Immunodeficiency - TOKA Flashcards
What is immunodeficiency?
Failure in humoral or cell mediated limbs of immune system
What is primary immunodeficiency?
A result of genetic defects in 1 or more components of immune system
- intrinsic defects in T or B cells
** usually genetic @ birth
What is secondary immunodeficiency?
Loss of function of antibody or lymphocytes
What genetic defects can lead to primary immunodeficiency? (8)
- Failure of pluripotent cells to differentiate (fetus cant develop)
- Failure of lymphoid lineage to differentiate from stem cells
- Lack of T cell development
- Lack of B cell development
- Blockage of B cells to make plasma cells
- Failure of plasma cells to make Ig classes
- Failure to make neutrophils + macrophages
- Failure to make complements components
What signs are suspected for primary immunodeficiency?
- Chronic or recurrent infection
- Multiple site infection in young
- Infection with foreign microorganisms
- Failure to respond to Antibiotic or chemo
- Lack of response to vax Ag
- Leukocytosis / Hypergammaglobinemia
- Leukopenia / Hypogammaglobulinemia
How can you diagnose primary immunodeficiency?
- Necropsy of dead litter mates
- Bone marrow / LN biopsy
- Detect complement proteins in serum
- Screen for infectious dz
- Determine CD4/CD8+ ratio
- Test for neutrophils/macrophages
- Assess type IV hypersensitivity
What syndrome causes a defect in the LYST gene? What does this lead to?
Chediak- Higashi syndrome (CHS)
Leads to formation of large secretory lysosomes in neutrophils, eosinophils, etc. which fuse, rupture, and cause tissue damage
Can cause cataracts
Chediak- Higashi syndrome is a ______ mutation
Missense - replaces Histidine with Arginine
A functional lyst gene is responsible for ___________
regulating lysosomal membrane trafficking
moving neutrophils, etc from blood to tissues
What is the clinical presentation of Chediak- Higashi syndrome?
- Loss of skin color
- dilution of hair pigment
- Cataracts
- Photophobia
- Increased susceptibility to infections + tumors bc reduced neutrophils
** - Abnormally bleeding + hematomas @ injection sites
A dog comes in for an annual vaccination. After giving the injection, the dog starts bleeding alot at the site of injection. You finally get the bleeding to stop and the dog goes home. The next day the dog comes in with a huge hematoma. What is suspected?
Chediak- Higashi syndrome
Abnormal bleeding and hematomas can cause death by acute hemorrhage
How can you diagnose Chediak- Higashi syndrome?
Blood smear of enlarged granules in neutrophils
Which cells are dysfunctional in CHS?
NK cells, Neutrophils, CD8+ Cytotoxic T cells
Which autoimmune disease can be seen due to a lack of Integrin CD11b/CD18 (Mac 1) ?
Canine leukocyte adhesion deficiency (CLAD) / BLAD in cows
What happens when a dog has CLAD?
- Neutrophils/Leukocytes dont have integrin so they cant extravasate to the tissues from blood
- Animal can die due to severe infections
What levels of neutrophils and eosinophils would you expect to see in the blood of a dog with CLAD and why?
Increased neutrophilia
Because neutrophils cant leave blood to go to the tissues bc NO INTEGRIN
What dog breeds are most susceptible to CLAD?
Irish Red and White setters
CLAD is a _________ mutation
Missense - Cysteine is replaced with serine
*** as a result CD11b is not expressed because the Beta chain of CD18 is not expressed
With canine cyclic neutropenia, there is a defect in the ______ gene which is responsible for ____________
AP3B1 gene
Responsible for trafficking of granular proteins like elastase to cytoplasmic granules during HEMATOPOIESIS
What is the result of Canine cyclic neutropenia?
Cyclic arrest of maturing myeloid progenitor cells in bone marrow
What do you expect to see with neutrophils in Canine Cyclic Neutropenia?
Fluctuating #s of neutrophils in peripheral blood
Loss of neutrophils every 11-12 days
- leads to abnormal imflamm. rxn and recurrent BacT and Fungal infections
Canine Cyclic Neutropenia results in neutrophils having a reduced __________ activity
Myeloperoxidase
What is an autosomal recessive disease in Border collies?
Canine Cyclic Neutropenia
appears after weaning and causes a gray/silver hair coat
Prolonged antibiotic therapy of Canine Cyclic Neutropenia leads to ________
Amyloidosis
Severe Combined Immunodeficiency Disease (SCID) in horses + dogs is from inheritance of an ______________ trait
Autosomal recessive trait
SCID is from a defect in ____________
DNA- dependent protein kinase catalytic subunit (DNA-PKcs)
What disease is caused by a mutation that removes 5 nucleotides leading to a loss of 967 AA?
SCID
SCID results in
***** no recombination of variable regions of TCR and BCR !!!!!
so lymphocytes cant recognize Ag
** lack of sufficient T and B cell production, low numbers in circulation (lymphopenia)
Would you expect to see high or low numbers of T and B lymphocytes in the blood of a horse with SCID?
LOW NUMBERS of T and B cells in circulation
What cells will be functional in a horse with SCID?
Neutrophils, NK cells, and monocytes
Bc these dont need recombination receptors!
How can you diagnose SCID in horses?
- Low circulating lymphocytes
- Lack of IgM in serum before suckling
- Hypoplasia of primary and secondary lymphoid organs
** no germinal centers or PALS in speen!
Which dog breed is susceptible to SCID?
Jack russels
SCID in dogs can cause?
- Lymphopenia
- Agammaglobulinemia (No Ab)
- Hyperplasia of primary and secondary lymph organs
What immunodeficiency is seen exclusively in males and is most common in corgis and bassets?
X-SCID
X-linked severe combined immunodeficiency
*** Lack of lymphnodes!!!!
X-SCID is from a mutation in the gene encoding _________
y-chain of the IL-2 receptor
**lymphocytes are not reactive in the presence of IL-2 :(
X-SCID is a _______ type of mutation
Nonsense muation
- results in STOP codon that produces a non functional protein
What cell is unaffected by X-SCID?
B cells will be present - but no class switching to IgG or IgA
How will X-SCID affect antibodies?
Normal IgM but reduced or lack of IgG and IgA
cant Ig class switch
What is the most common selective Ig isotype deficiency?
IgA deficiency
What Ig deficiency can be found in King charles spaniels?
IgG deficiency
Selective IgA deficiency can lead to _______
Antiobiotic resistance
** NOT BECAUSE OF LACK OF IgA
** DUE TO constant bacT infections with continuous treatment
Canine distemper virus attacks __________
T and B cells in tonsils, bronchial LNs and blood
** has the same CD150 receptor as lymphocytes - binds and destroys them
FeLV has a tropism to ________
lymphoid tissue
FIV acts by
Activating T regs to suppress immune system + increase IL-10 production
Reduces IL-2 and CD4+ T cells
FeLV acts by
-Attacking T cells + reducing # of CD4+ T cells
- Wasting syndrome - atrophy of thymus
- Atrophy or hyperplasia of lymphoid tissue
- Supresses immune system
FIV binds to _______ on activated CD4+ T cells
CD134 and CD184
Canine distemper virus binds to ____ on activated T cells and leads to virus replication and destruction of the cell
CD150
Viruses can damage primary or secondary lymphoid organs leading to _________
- Lymphopenia
- Reduction of lymphocyte reactivity
- Hypogammaglobinemia
Secondary immunodeficiences can be due to:
- Infectious agents like viruses (FIV, FELV)
- Toxins
- Stress
- Malnutrition
- Old age (immunosenescence)
Common Variable Immunodeficiency (CVID) can lead to
B cells not producing sufficient Ig
This can cause recurrent infections
________ defect appears in order horses, over 4 years of age and is due to lack of stimulation of B cells by CD4+ T cells
Common variable immunodeficiency (CVID)
Why does antibiotic resistance occur with selective IgA deficiency in dogs?
Because of constant bacT infections and continuous treatments with antibiotics
In FIV, what cell type is reduced?
CD4+ T cells
Immunodeficiences associated with innate immunity may involve defects in __________
- Lack of Phagocytosis
- Lack of complement
- Dysfunctional NK cells
With SCID, why are foals born healthy but develop health problems around 2 months of age?
Because they have passive immunity from mom, but that wears off and the baby has T and B cells with no recombination (No Ag specificity) and cant recognize Ag
