PID Flashcards
1
Q
What are the 8 warning signs of immunodeficiency disorder?
A
- 8+ ear infections in 1 year
- 2+ serious sinus infections in 1 year
- 2+ pneumonia infections in 1 year
- 2+ deep-seated infections, or infections in unusual areas
- recurrent deep skin or organ abscesses
- need for IV antibiotic therapy to clear infection
- infections with unusual or opportunistic organisms
- family history of primary immunodeficiency
2
Q
Percentages of PID’s:
- humoral B cell:
- combined B and T cell:
- phagocytic:
- cellular T cell:
- complement:
A
- humoral B cell: 50%
- combined B and T cell: 20%
- phagocytic: 18%
- cellular T cell: 10%
- complement: 2%
3
Q
If a patient has recurrent sinopulmonary bacterial infections, what branch of the immune system should you screen?
A
humoral immunity
4
Q
If a patient has recurrent viral and/or fungal infections, what branch of the immune system should you screen?
A
cellular immunity
5
Q
If a patient has recurrent skin abscesses and/or fungal infections, what branch of the immune system should you screen?
A
phagocyte defect
6
Q
If a patient has bacteremia or meningitis with encapsulated bacteria, what branch of the immune system should you screen?
A
complement deficiency
7
Q
Testing for PID
- lab test: differential count of blood cells (CBC)
- screens for:
- what to look for:
A
- T cell, B cell, T/B cell defects
- decreased numbers of T cells, B cells, or platelets
8
Q
Testing for PID
- lab test: DTH skin test
- screens for:
- what to look for:
A
- T cell defects
- negative or possible impaired T cell response
9
Q
Testing for PID
- lab test: serum IgG, IgM, or IgA
- screens for:
- what to look for:
A
- humoral immunodeficiency
- decrease in any or all immunoglobulins
10
Q
Testing for PID
- lab test: antibody testing to specific antigen after immunization
- screens for:
- what to look for:å
A
- humoral immunodeficiency
- decrease or absent antibody response to vaccination
11
Q
Testing for PID
- lab test: total hemolytic complement assay
- screens for:
- what to look for:
A
- complement deficiency
- decrease or absent components in classical pathway
12
Q
Testing for PID
- lab test: nitroblue tetrazolium test
- screens for:
- what to look for:
A
- phagocytic disorder
- abnormal test result
13
Q
What are the 3 main deficiencies present in B, T, and NK cell development that may lead to SCID’s?
A
- adenosine-deaminase deficiency: ADA converts toxic deoxyadenosine into deoxyinosine, which is not harmful
- artemis gene-product deficiency: artemis is an enzyme in VDJ recombination that serves to repair double strand breaks
- RAG1 and RAG2 deficiency: enzymes necessary for recombination
14
Q
- this condition is a/w profound deficiencies of T cell and B cell functions, and sometimes NK cell function
- typically a/w severe lymphopenia
- characterized by severe opportunistic infections (chronic diarrhea, failure to thrive)
- fetus with this condition is at risk of abortion due to inability to reject the maternal T cells that may cross the placenta into fetal circulation
- patients with this condition should avoid all live vaccines
A
severe combined immune deficiencies (SCID’s)
15
Q
- the first immunodeficiency in which the specific molecular defect was indentified
- autosomal recessive disorder
- absent or low IgG, IgA, and IgM
- immunophenotype: T-, B-, NK-
- second most common cause of SCID (15%)
- this enzyme is essential for metabolic function of various cells, especially T cells
- this deficiency leads to accumulation of toxic (for lymphocytes) deoxyadenosine
- tx: hematopoietic stem cell transplantation (HSCT)
(avoid all live viral vaccines)
A
adenosine deaminase (ADA) deficiency
16
Q
- rare, autosomal recessive condition that accounts for 4% of all SCID cases
- normal IgG, IgA, and IgM levels
- immunophenotype: T-, B+, NK+/-
- leads to accumulation of intracellular deoxyguanosine triphosphate (dGTP), toxic for lymphocytes, leading to decrease in peripheral T cell numbers, but B cell numbers are normal
- onset can occur during infancy (classic SCID phenotype) or later in life with a milder form
- autoimmune disorders also caused by this deficiency: hemolytic anemia, thyroid dz, arthritis, lupus
- tx: HSCT
(avoid all live viral vaccines)
A
purine nucleoside phosphorylase (PNP) deficiency
17
Q
- rare, autosomal recessive radiosensitive cause of SCID
- absent or low IgG, IgA, and IgM
- immunophenotype: T-, B-, NK+
- presentation occurs in infancy: diarrhea, candidiasis, opportunistic infections (pneumocystis jiroveci)
- T and B cells are absent, NK cells are normal
- patients at increased risk of developing lymphomas
- dx: immunophenotype and radiosensitivity
- tx: HSCT
(avoid all live viral vaccines)
A
artermis deficiency
18
Q
- rare, autosomal recessive disorder causing SCID
- absent or low IgG, IgA, and IgM
- immunophenotype: T-, B-, NK+
- causes impaired V(D)J recombination, leads to defective expression of pre-TCR and pre-BCR
- presentation occurs in infancy: diarrhea, candidiasis, opportunistic infections (pneumocystis jiroveci)
- leaky defects: partial function of RAG1/RAG2 and leads to Omenn syndrome: severe erythroderma, splenomegaly, eosinophilia, and high IgE
- tx: HSCT
(avoid all live viral vaccines)
A
RAG1/RAG2 deficiency
19
Q
- autosomal recessive trait that leads to 7% of all SCID cases (boys and girls equally affected)
- very low IgG, IgA, and IgM
- immunophenotype: T-, B+, NK-
- causes defect in IL-2 receptor signaling
- tx: HSCT
(avoid all live viral vaccines)
A
Janus kinase 3 (Jak3) deficiency
20
Q
- classic example of T cell deficiency
- normal IgG, IgA, and IgM
- immunophenotype: T-, B+, NK+
- most cases result from deletion of 22q11.2 region (contains 35 genes), low T cell numbers present in 80% of patients w/ this deletion
- humoral immunity intact in most patients
- classic triad: cardiac anomalies, hypocalcemia, hypoplastic thymus
- patients commonly suffer from frequent upper respiratory infections
- live viral vaccines can be given to patients who have CD8+ T cell count >300 cells/mm3
A
DiGeorge syndrome (DGS)
21
Q
- most commonly inherited as an X-linked trait linked to mutation in Bruton tyrosine kinase (BTK)
- autosomal recessive forms also exist
- early B cell development (pre BCR) is arrested at the pre-B cell stage
- leads to absent or low levels of circulating B cells
A
agammaglobulinemia
22
Q
- X-linked disorder with a freq of approx 1:250,000 males
- no IgG, IgM, or IgA
- immunophenotype: B-, T+, NK+
- mutation in tyrosine kinase that causes defect in rearrangement of Ig heavy chain genes
- dx: 5-6 month old infants, titers of serum antibodies are totally absent or very low
- tx: HSCT
A
X-linked Btk deficiency
23
Q
- decreased concentrations of one or more IgG subclasses
- some IgG subclasses low, normal IgM, IgA, and IgE
- immunophenotype: B+, T+, NK+
- caused by defects in several genes
- usually asymptomatic, may be a/w recurrent viral/bacterial infections, involving respiratory tract
- low levels of IgG2 are freq a/w poor responses to polysaccharide antigens in children
- IgG4 levels vary widely and many healthy people have no IgG4
A
isolated IgG subclass deficiencies
24
Q
- no IgA, normal IgG and IgM
- immunophenotype: B+, T+, NK+
- high prevalence (1 in 700), males more likely have, most affected individuals are healthy
- multiple genes involved
- dx: more than 85% with recurrent infections, typically encapsulated bacteria; dx by antibody titers
- 50% of patients are asymptomatic, as IgM is able to translocate across mucosal epithelium
- patients often develop autoimmune dz’s and allergies
- patients may have anti-IgA IgG, which has been linked to development of non-IgE mediated anaphylaxis in response to intravenous immunoglobulin (IVIG) transfusion
A
IgA deficiency
25
- high IgM, low IgG and IgA
- immunophenotype: B+, T+, NK+
- patients have increased susceptibility to bacterial infections
- example: CD40L mutation, causes lack of class switching or somatic hypermutation
- X-linked CD40L deficiency (males) responsible for 2/3 of cases
- autosomal CD40 deficiency (females and males) responsible for 1/3 of cases
- tx: HSCT
hyper IgM (HIGM) syndrome
26
- low IgG/IgA, IgM normal or low
- immunophenotype: B+, T+, NK+
- infant IgG production delayed up to 36 months, majority of patient's Ig conc normalize between 2-4 y/o
- results in increased susceptibility to sinopulmonary infections
transient hypogammaglobulinemia of infancy
27
- low IgG and IgA, sometimes low IgM
- immunophenotype: B-/+, T+, NK+
- autosomal disorder that occurs in 1:25,000 individuals
- mutations may occur in receptor for B cell growth factors (maturation/activation) and costimulators (T-B collaboration)
- number of circulating B cells is reduced or normal, B cells fail to differentiate into plasma cells
- onset: after 4-5 years of age, dx usually around 20-30 y/o
- sx: recurrent infections, autoimmune dz, lymphomas
- tx: HSCT
- dx: history of recurrent pyogenic sinopulmonary infections
common variable immune deficiency (CVID)
28
- very low IgG, IgA, and IgE
- immunophenotype: T-, B+, NK-
- most common form of SCID (45% of all cases)
- X-linked recessive
- mutation in the gene that encodes for γ chain shared by the T-cell growth factor receptor (IL-2Rγ) and other growth factor receptors
- IL-2Rγ is shared with other cytokine receptors including IL-4, IL-7, IL-9, IL- 15, and IL-21
- no funtional B cells since T cells are unable to "help"
- sx: failure to thrive, severe thrush, opportunistic infections, chronic diarrhea
- tx: HSCT
(avoid all live viral vaccines)
common γ chain deficiency (γC or IL-2Rγ)
29
- very low IgG, IgA, IgE
- immunophenotype: T-, B+, NK+
- autosomal recessive
- low antibody levels due to absence of T cell costim signaling
- onset: childhood
- sx: candidiasis, chronic diarrhea, pneumocystis jiroveci pneumonia, severe viral infections
- sx: sequencing of IL-7α gene
- tx: HSCT
(avoid all live viral vaccines)
IL-7Rα chain deficiency
30
- variable hypogammaglobulinemia
- immunophenotype: T+, B+, NK-
- rare, autosomal recessive disorder causing HLA II negative SCID
- no MHC II on APC's causes deficiency in CD4+ T cells
- genes from MHC II on chromosome 6 are intact, mutations are in genes that encode for transcription factors that regulate expression of MHC II genes
- mainly low levels of IgA and IgG2
- sx: recurrent respiratory, GI, and urinary tract infections, death in early childhood
- tx: HSCT
bare lymphocyte syndrome type 2 (BLS II)
31
- immunophenotype: T+, B+, NK+
- caused by mutation in TAP1 molecules that transfer peptides to ER
- CD8+ cells and NK cells are functionally deficient, CD4+ cells are normal, normal antibody prod, normal DTH
- sx: recurring viral infections
- tx: HSCT not recommended
MHC class I deficiency
32
- low IgG, IgA, and IgM
- immunophenotype: T-, B+, NK+
- autosomal recessive form of SCID caused by deficieny of the CD3 subunits
- presents in infancy w/ lymphopenia and decreased T cell numbers, B and NK cells are normal
- antibody responses typically decreased
- sx: failure to thrive, opportunistic infections, diarrhea
- tx: HSCT
CD3 complex deficiencies
33
- defect in T cell function
- self reactive T effector cells are not inhibited because of a mutation in FoxP3
- results in loss of inhibition by CD+CD25+ Treg cells
- HSCT is curative and should be considered
immunodysregulation, polyendocrinopathy and enteropathy X-linked syndrome (IPEX)
34
- defect in T cell function
- defects in either Fas, FasL, caspase-8, or caspase-10 genes results in abrogated formation of the death-inducing signaling complex (DISC) and resistance of effector T cells to apoptosis
- HSCT not recommended
autoimmune lymphoproliferative syndrome (ALPS)
35
- low IgM, normal IgG, elevated IgA and IgE
- immunophenotype: T-, B+, NK-
- X-linked disorder caused by mutations in WAS protein
- patients develop combined immunodeficiency: decreased IgM, normal IgG, elevated IgA and IgE; T cell lymphopenia; decreased NK cell cytotoxicity
- sx: thrombocytopenia, eczema, autoimmune dz, malignancy, recurrent bacterial infections (encap bacteria), viral infections, opportunistic infections (P. jiroveci and candida)
Wiskott-Aldrich syndrome (WAS)
36
Mutations resulting in increased susceptibility to nontuberculous mycobacteria have been identified in the genes encoding: (3)
- the IFN-γ receptor
- the IL-12 receptor
- the p40 subunit of IL-12
37
What happens when there are defects in the IL-12/IFN-γ pathway?
(IL-12 signaling is essential for differentiation of naive T cells in Th1 cells)
- mutations in IL-12 or IL-12R genes result in clinically limited primary immunodeficiency
- patients do not produce Th1 cytokine IFN-γ, necessary for control of intracellular bacterial infections
- sx: selective susceptibility to intracellular pathogens (atypical mycobacteria, candida, salmonella)
- patients have defects in Th17 cells that accounts for recurrent fungal infections
38
- deficiency that leads to unusual susceptibility to chronic mucocutaneous candidiasis
- a/w mutations in genes encoding for either IL-17, IL-17R or transcriptional factors STAT1, STAT3, or AIRE
- many patients prior were categorized into having hyper IgG syndrome due to severe atopic disease (atopic dermatitis, food allergies, asthma) and recurrent staph aureus skin abscesses
Th17 deficiency
39
- can be caused by mutations in multiple genes
- 2 major types: classical (CNKD) and functional (FNKD)
- classical: absence of NK cells (ex: GATA2 deficiency)
- functional: presence of NK cells exhibiting defective NK cell activity w/o NK lymphopenia (ex: perforin deficiency)
- sx: multiple severe or disseminated viral infections, herpes infections, varicella pneumonia, disseminated cytomegalovirus (CMV), HSV
NK cell deficiency (NKD)
40
- most frequent phagocytic disorder characterized by the tendency to form granulomas
- more common in males
- enzymatic deficiency of NADPH oxidase in phagocytes, fail to generate superoxide anion and other O2 radicals
- results in defective elimination of extracellular pathogens (bacteria, fungi)
- patients are susceptible to reccurent infection w catalase-positive organisms (e.g. staph)
chronic granulomatous disease (CGD)
41
- X-linked recessive genetic disease a/w anemia
- lack of substrate for NADPH
- more individuals are asymptomatic
- manifestation: tendency to form granulomas
G6PD deficiency
42
- caused by mutations in CD18 gene resulting in defective or deficient β-2 integrin
- neutrophil count is 2x normal amnt, neutrophils unable to aggregate, they cannot bind to intercellular adhesion molecules on endothelial cells
- defective migration of neutrophils, inable to move to site of infection/injury
- infected foci contain few neutrophils and heal slowly with enlarging borders and dysplastic scars
- sx: recurrent infections of oral and genital mucosa, skin, intestinal, and respiratory tracts
- clinical manifestations: delayed detachment of umbilical cord, slow wound healing, severe bacterial infections, failure to form pus
- prognosis: poor w/ early death
- dx: flow cytometric assessment of neutrophil adhesion molecules CD11 and CD18
leukocyte adhesion deficiencies (LAD)
43
- autosomal recessive disorder
- patients become wheelchair bound and usually die of infection in early 30's
- molecular defect is in structure of neutrophil granule as abnormal giant granules, granules do not contain cathepsin G and elastase
- defects manifested in abnormal chemotaxis and degranulation
- patients are prone to pyogenic granulomas cause by bacterial infections
- response to infection is blunted neutrophilia due to delayed diapedesis
- biphasic immunodeficiency: first phase susceptibility to infections, second phase accelerated lymphoproliferative syndrome (hepatosplenomegaly and lymphadenopathy)
- dx: azurophilic giant cytoplasmic inclusions in blood cells, partial albinism, no NK activity
Chediak-Higashi syndrome
44
- deficiency linked to development of SLE and RA
- deficiency in complement system leads to immune complexes growing too large to be cleared
- complexes form desposits in tissues and become site of inflammation
C1 and C4 deficiency (sometimes C2)
45
- deficiency in complement system that results in recurrent sinopulmonary infections
- most common complement def in Caucasian pops
C2 deficiency
46
defects in C3 result in a clinical phenotype that is indistinguishable from _______ deficiencies, although this complement deficiency is markedly less frequent than ______ \_\_\_-dependent immunodeficiencies
- antibody
- humoral ab
47
- autosomal recessive inheritance
- increased susceptibility to Neisserial infections
- cause of low levels of complement protein: inherited, acquired, complement consumption due to chronic comp activiation due to ongoing infection
- dx: absent C8 levels in presence of normal C3 and C4 values suggests C8 deficiency; absent C8 levels in presence of low C3 and C4 values suggests complement consumption
MAC deficiencies
48
- causes hereditary angioedema (HAE)
- sx: recurrent swelling in extremities, lips, face, larynx, and GI tract
- swelling due to prod of bradykinin, a by-prod of kinin-generating pathway
- tx: C1 inhibitor replacement therapy
C1-INH deficiency
49
- condition related to failure to regulate formation of MAC
- somatic mutation causes deficiency of glycosylphosphatidylinositol (GPI)
- cells lack all the proteins (~40) linked through GPI anchor to their cell membranes
- two most important: DAF (CD55) and CD59, which are complement regulatory proteins involved in protecting RBC's from complement action
- cause of intravascular hemolysis in patients is increased susceptibility of RBC's to complement
paroxysmal nocturnal hemoglobinuria (PNH)
50
- innate immune deficiency that results in impaired signaling for all TLR's, except TLR3
- leads to abnormally frequent and severe infections by pyogenic bacteria
- patients have normal resistance to other common bacteria, viruses, fungi, and parasites
- patients lack fevers and elevated levels of ESR/CRP despite active infection
- during infection, blood levels of TNF-α, IL-1, and IL-6 are low
(TLR3 deficiency is autosomal dominant disorder which results in increased susceptibility to HSV encephalitis)
MyD88 deficiency
