Immunodeficiencies Flashcards
Name the affected genes, immune defect, susceptibility for asplenia
Affected genes=> not known
immune defect=> absence of the spleen
susceptibility=> encapsulated extracellular bacteria
Name the affected genes, immune defect, susceptibility for C3 deficiency
Affected genes=> C3
immune defect=> lack of C3
susceptibility=> recurrent infeciton with gram (-) bacteria
Name the affected genes, immune defect, susceptibility for paroxysmal nocturnal hemoglobinuria
Affected genes=> somatic and germline mutations in genes involved in phosphatidylinositol glycan biosynthesis
immune defect=> lack of DAF, HRF, and CD59
susceptibility=> lysis of erythrocytes by complement
Name the affected genes, immune defect, susceptibility for X-linked hypohidrotic ectodermal dysplasia and immunodeficiency
Affected genes=> NEMO
immune defect=> impaired activation of NFkB
susceptibility=> chronic bacterial and viral infections
Name the affected genes, immune defect, susceptibility for chronic granulomatous disease
Affected genes=> NADPH oidase
immune defect=> impaired neutrophil function
susceptibility=> chronic bacterial and fungal infections
Name the affected genes, immune defect, susceptibility for MBL deficiency
Affected genes=> MBL
immune defect=> lack of MBL
susceptibility=> susceptibiity to meningitis due to Neisseria meningitidis
Name the affected genes, immune defect, susceptibility for NK cell deficiency
Affected genes=> not known
immune defect=> absence of NK cells
susceptibility=> susceptibility to herpes virus infections
Name the affected genes, immune defect, susceptibility for X-linked hyper IgM syndrome
Affected genes=> AID or CD40L or CD40 or NEMO
immune defect=> no isotype switching or somatic hypermutation in B cells
susceptibility=> extracellular bacterial and fungal infections
Name the affected genes, immune defect, susceptibility for SCID
Affected genes=> RAG1 or RAG2
immune defect=> no gene rearrangements in B and T cells
susceptibility=> all types of infections
Name the affected genes, immune defect, susceptibility for Omenn syndrome
Affected genes=> RAG1 or RAG2 or Artemis
immune defect=> Impaired RAG function
susceptibility=> all types of infections
Name the affected genes, immune defect, susceptibility for bare lymphocyte syndrome
Affected genes=> TAP1 or TAP2
immune defect=> low MHC class I expression
susceptibility=> respiratory viral functions
Name the affected genes, immune defect, susceptibility for pre-B cell receptor deficiency
Affected genes=> lambda 5
immune defect=> lack of B cells and Abs
susceptibility=> persistent bacterial infections
Name the affected genes, immune defect, susceptibility for X-linked agammaglobulinemia
Affected genes=> Bruton’s kinase (BtK)
immune defect=> B cells blocked at pro-B cell stage
susceptibility=> recurrent bacterial infections
Name the affected genes, immune defect, susceptibility for Complete DiGeorge’s syndrome
Affected genes=> not known
immune defect=> absence of the thymus and T cells
susceptibility=> All types of infections
Name the affected genes, immune defect, susceptibility for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
Affected genes=>AIRE
immune defect=> reduced T cell tolerance to self antigens
susceptibility=> autoimmune diseases
Name the affected genes, immune defect, susceptibility for IPEX
Affected genes=> FOXP3
immune defect=> lack of regulatory t cells and peripheral tolerance
susceptibility=> autoimmune diseases
Name the affected genes, immune defect, susceptibility for ZAP-70 deficiency
Affected genes=> ZAP70
immune defect=> T cells that cannot signal through their receptors
susceptibility=> all types of infection
Name the affected genes, immune defect, susceptibility for Autoimmune lymphoproliferative syndrome
Affected genes=> Fas or FasL
immune defect=> englarged spleen and lymph nodes
susceptibility=> lymphomas and autoimmunities
Name the affected genes, immune defect, susceptibility for IgG2 deficiency
Affected genes=>not known
immune defect=> lack of IgG2
susceptibility=> encapsulated bacteria
Name the affected genes, immune defect, susceptibility for selective IgA deficiency
Affected genes=> not known
immune defect=> lack of IgA
susceptibility=> no major susceptiblility
Why are patients with asplenia especially susceptible to septic infections?
the spleen is one the blood filters and splenic macrophages take up bacteria in the blood
so when the spleen is not present (congential or acquired) then especially susceptible to encapsulated bacteria
What is the best treatment for asplenia patients?
vaccination for encapsulated bacterial pathogens
prophylactic antibiotic treatment prior to dental procedures or on showing symptoms of respiratory infection/fever
Why do inherited phagocyte defects lead to infection?
can have profound effct on the capacity of the host ot clear bacterial infections
What are the inherited phagocyte defect disease? (5)
- Leukocyte adhesion deficiency
- Chronic granulomatous disease
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Myeloperoxidase deficiency (catalyzes production of hypochlorous acid)
- Chediak-Higashi syndrome
What is the cellular abnormality, immune defect, and associated infections and other diseases of LAD?
Cellular abnormality=> Defective CD18
Immune defect=> defective migration of phagocytes into infected tissues
associated infections and other diseases=> widespread infections with capsulated bacteria
What is the cellular abnormality, immune defect, and associated infections and other diseases of CGD?
Cellular abnormality=> defective NADPH oxidase. phagocytes cannot produce O2
Immune defect=> impaired killing of phagocytosed bacteria
assoc. infections and other diseases=> chronic bacterial and fungal infections and granulomas
What is the cellular abnormality, immune defect, and associated infections and other diseases of G6PD deficiency?
Cellular abnormality=> Deficiency of G6PD and defective respiratory burst
Immune defect=> impaired killing of phagocytosed bacteria
assoc. infections and other diseases=> chronic bacterial and fungal infections which can cause anemia inducing by certain agents
What is the cellular abnormality, immune defect, and associated infections and other diseases of Myeloperoxidase deficiency?
Cellular abnormality=> deficiency of myeloperoxidase in neutrophil granules and macrophage lysosomes and impaired production of toxic oxygen species
Immune defect=> impaired killing of phagocytosed bacteria
assoc. infections and other diseases=> chronic bacterial and fungal infections
What is the cellular abnormality, immune defect, and associated infections and other diseases of Chediak-Higashi syndrome?
Cellular abnormality=> defect in vesicle fusion
Immune defect=> impaired phagocytosis due to inability of endosomes to fuse with lysosomes
assoc. infections and other diseases=> recurrent and persistent bacterial infections. granulomas. effects on many organs
What is a disorder characterized by low numbers of granulocytes with count of less than 500 cells/uL? What are the 3 most important types?
neutropenia
severe congenital neutropenia (kostmann syndrome)
cyclic neutropenia
benign chronic neutropenia
Kostmann syndrome is a neutropenia. Name its inheritance pattern, what is effected, and what will be damaged
autosomal recessive disorder
disorder with a gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR)
G-CSF stimulates granulocyte growth
What are some primary immunodeficiencies that have an associated neutropenia? What do some patients with these disorders produce?
- X-linked hyper-IgM syndrome
- XLA
- WHIM
- Griselli
neutrophil-specific autoAbs that cause neutropenia
What are the 3 NK cell deficiencies? What is necessary for this diagnosis?
- Absolute NK cell deficiency (ANKD)
- classical NK cell deficiency (CNKD)
- functional NK cell deficiency (FNKD)
flow cytometry for NK cells and NKT cells helps diagnose
How are NK cell deficiencies presented?
highly variable but typically with increased incidence and severity of viral and other infections especially from
varicella zoster virus, herpes, cytomegaloviruses, EBV
MAI and other opportunistic pathogens
Trichophyton (fungus)
The genetic deficiency in NK cell deficiencies are what?
defective formation of cytoplasmic granules
defective perforin
defects in development in bone marrow
What deficiency would disrupt NFkB activity? Why is this significant?
NEMO deficiency
(also called X-linked hypohydrotic ectodermal dysplasia and immunodeficiency)
NFkB is an important transcription factor for physical development as well as innate immunity
How does a NEMO deficiency disrupt innate immunity? (specific)
most TLR signaling activates NFkB which controls cytokine expression
What is the immunodeficiency of a NEMO deficiency and how should be treated?
patiens suffer from recurrent bacterial and viral infections (MAI is a common opportunistic pathogen involved)
biweekly injections of gamma globulin from a healthy donor; bone marrow transplant
What are the 2 general deficiences of inherited complement? and what is the associated result?
deficiences of each of complement proteins identified and susceptibility to extracellular bacteria is result
deficiencies of complement reg proteins can cause problems that leave a
- susceptibility to encapsulated bacteria (depletion of C3)
- autoimmune-like disease complement activity destroys RBCs
C1, C2 and C4 deficiency causes what?
immune complex disease
What is a deficiency in C3 cause?
susceptibility to capsulated bacteria
What would a deficiency in C5-C9 cause?
susceptibility to Neisseria
What would a deficiency in Factor D, or properdin cause?
susceptibility to capsulated bacteria and neisseria but no immune complex disease
What would a deficiency of Factor I cause?
similar effects to deficiency of C3
What would a deficiency in DAF or CD59 cause?
autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria
What would a deficiency in C1INH cause?
herdeitary angioneurotic edema (HANE)
will not allow dissociation from C1 from C1q
remember that C1INH controls spontaneous activation of C1 that always occurs
What is the clinical presentation of MBL deficiency?
experience recurrent severe infections
What does paroxymal nocturnal hemoglobinuria result from? How does this present?
- genetic deficiecy of glycophosphatidylinositol which is required for surface expression of CD59 and DAF
- MAC formation disrupted
presents with complement induced intravascular hemolytic anemia, red urine, thrombosis
What are the inherited Ab deficiencies? What do all these diseases result in? How are they treated?
- XLE,
- pre-B cell receptor deficiency
- X-linked hyper IgM syndrome
- selective IgA deficiency
- selective IgG deficiency
Result => Ab deficiencies result in susceptibility to extracellular bacteria, especially encapsulated bugs that are resistant to phagocytosis
Treatment => montly injections of gamma globulin from healthy donors
How does XLA affect B cell development? What is the final result?
it is a defect in a protein tyrosine kinase (Bruton’s tyrosine kinase) that is involved in the signal transduction for B cell development
NO HUMORAL IMMUNE SYSTEM so susceptible to extracellular pathogens and many viruses
What does a pre-B cell receptor deficiency lead to?
non-functional surrogate light chain results is inability of developing B cells to produce a pre-BCR
they all undergo apoptotic death
susceptible to extracellular and viral pathogens
X-linked hyper IgM syndrome can be casued by what 2 mechanisms?
- Defect in T helper function stemming from a defect in CD40 ligand expression so B cells do not receive secondary activation signal
- caused by activation-induced cytidine deaminase deficiency (AID) because it is required for isotype switching and somatic hypermutation
if you have a selective IgA deficiency, what are you susceptible to?
parasite pathogens
If you have a selective IgG deficiency in IgG1, what are you susceptible to?
bacterial and viral pathogens
very rare
In an IgG2 deficiency, what are patients susceptible to?
encapsulated bacteria
most common in kids
What is the most common primary immunodeficiency disorder?
common variable immunodeficiency
What are the 3 types of defects in CD8 T cell function?
TAP peptide transporter deficiency
CD8 alpha chain defect
non-sense mutation of perforin
What is the result TAP peptide transporter deficiency and CD8 alpha chain defect?
they both have the same phenotype associated with lack of CD8 expression due to no (+) selection during thymic development
deficient in response to intracellular pathogens associated with low levels of MHC I
If you have no TAP, then you have no what gene products?
HLA
What is the result of a non sense mutation of perforin?
- dramatically or totally reduced CTL activity
- NORMAL NUMBERS OF CD8
- unable to induce programmed cell death of target cells
What other immune cell type have reduced function in non-sense mutation in perforin?
CTL, effector cells, NK cells
What defects result in SCID(severe combined immune deficiency) phenotype? why?
CD4+ T cell
critical to bother Ab-mediated and cell-mediated immune responses
What are the diseases that lead to SCID as a result of T cell function?
- bare lymphocyte syndrome
- Wiskott-Aldrich syndrome
- adensoine deaminase (ADA) or purine nucleotide phosphorylatse deficiency
- common gamma chain deficiency
- Jak3 deficiency
- CD3 deficiency
What is bare lymphocyte syndrome caused from?
lack of expresion of mHC class II molecules
Wiskott-aldrich syndrome is a defect in T cell function leading to SCID. What is defected in this disease?
cell cross-talk deficiency
defect in cytoskeletal reorganization needed for T cells to deleiver cytokines and other signals to B cells and macrophages
ADA is a defect in T cell function leading to SCID. What is the result of this defect?
accumulation of toxic nucleotide catabolites that kills developing B and T cells
Common gamma chain deficiency is caused by a defect in T cell function leading to SCID. What is impaired and what is the result? What is the most important deficiency cytokine altered?
gamma chain makes up many signaling components and interactes with Jak3
**impaired signaling results in failure of T cells to proliferate **
NO effector cells
**IL-2 which promotes T cells **
Jak 3 deficiency is caused by a defect in T cell function leading to SCID. What does it impair and the result?
impaired signaling results in failure of T cells to proliferate
NO effector cells
Name the diseases from defects in B and T cell function that lead to SCID
- Omenn
- patients develop fungal, bacterial, viral infections
- DiGeorge syndrome
- complete DiGeore syndrome
- ZAP-70 deficiency
*
Omenn syndrome is associated with defects in B and T cell function that causes SCID. What mutations are associated and what is the result?
mis-sense mutations that result in partially active RAG enzymes
results => absence of B cells and low numbers of oligoclonal autoreactive T cells
NO acquired immune response
Patients who evelop fungal, bacterial, and viral infections are typical of SCID and are generally a result in defects in B and T cell function. What is the associated phenotype?
impaired signaling results in failure of T cells to proliferate
NO effector cells
Which 3 diseases that cause skid have the same phenotype? what is the phenotype?
- common gamma chain deficiency
- Jak3 deficiency
- fungal, bacterial, viral infections
impaired signaling resulting in failure of T cells to proliferate
NO effector cells
DiGeorge’s syndrome is a defect in B and T cell function that causes SCID. What does it result from and what is its prevalence?
What characteristic phenotypes are shown?
results from small deletionin chromosome 22 with an incidence rate of 1/4000
phenotypes => congenital heart disease, palatal abnormalities, learning disabilities, hopocalcemia, mild facial differences
What is the primary difference in DiGeorge’s syndrome and complete DiGeorge’s syndrome?
“complete” is much more rare
complete => absent or underdeveloped (nonfunctional) thymus so very few/any T cells
ZAP-70 deficiency is a defect of B and T cell function leading to SCID. What causes this disease?
cause=> genetic defect that prevents expression of functional ZAP-70
What is ZAP-70 and what is it required for?
a tyrosine kinase that associated with phosphorylated ITAMs during signaling via the TCR
TCR is required for signaling via the TCR
Why do patients with a ZAP-70 deficiency result in SCID?
absence of CD8 T cells
normal amount but NON-FUNCTIONAL CD4 T cells
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a result of what deficiency? What is the phenotype of the patient?
autoimmune regulator (AIRE)=> transcription factor regulating expression of several hundreg host-tissue specific genes by epithelial cells in thymic medulla
results in development of a myriad of autoimmune syndromes
These host-specific proteins serve as a source of self-proteins for presentation during thymic negative selection
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) results from what deficiency? How would a patient present?
results from genetic deficiency of FoxP3 expression in regulatory CD4 T cells
presents in early onset autoimmunity to a variety of host tissue de to lack of Treg cell function
People with IPEX will complain most commonly of the clinical triad of what manifestations? Kids will display what other diseases?
- watery diarrhea
- eczematous dermatitis
- endocrinopathy (type I diabetes)
Most kids also display Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, tubular nephropathy
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic diseae characterized by what? What is the result of this disease?
lymphadenopathy and splenomegaly due to mutation that prevents expression of either Fas, FasL or caspase 10
results form immune cells failing to undergo apoptotic death following immune response
overpopulation of 2nd lymphoid tissue
Patients with ALPS often have a large number of what?and what will they present with?
large nuber of CD4- CD8- T cells (double negative)
present with hemolytic anemia, neutropenia, decresed platelets,
What does factor P do in the complement cascade?
binds to C3 convertase of the alternative pathway and stabilizes it
results in longer lived C3 convertase and lower deposition of C3b via the alternative pathway
What will factor I lead to?
down regulation of the immune system
What is the treatment for inherited Ab deficiencies?
monthly injections of gamma globulin from healthy donors
