PID

Question 1

What are the 8 warning signs of immunodeficiency disorder?

Answer 1

• 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

Question 2

Percentages of PID’s:

• humoral B cell:
• combined B and T cell:
• phagocytic:
• cellular T cell:
• complement:

Answer 2

• humoral B cell: 50%
• combined B and T cell: 20%
• phagocytic: 18%
• cellular T cell: 10%
• complement: 2%

Question 3

If a patient has recurrent sinopulmonary bacterial infections, what branch of the immune system should you screen?

Answer 3

humoral immunity

Question 4

If a patient has recurrent viral and/or fungal infections, what branch of the immune system should you screen?

Answer 4

cellular immunity

Question 5

If a patient has recurrent skin abscesses and/or fungal infections, what branch of the immune system should you screen?

Answer 5

phagocyte defect

Question 6

If a patient has bacteremia or meningitis with encapsulated bacteria, what branch of the immune system should you screen?

Answer 6

complement deficiency

Question 7

Testing for PID

• lab test: differential count of blood cells (CBC)
• screens for:
• what to look for:

Answer 7

• T cell, B cell, T/B cell defects
• decreased numbers of T cells, B cells, or platelets

Question 8

Testing for PID

• lab test: DTH skin test
• screens for:
• what to look for:

Answer 8

• T cell defects
• negative or possible impaired T cell response

Question 9

Testing for PID

• lab test: serum IgG, IgM, or IgA
• screens for:
• what to look for:

Answer 9

• humoral immunodeficiency
• decrease in any or all immunoglobulins

Question 10

Testing for PID

• lab test: antibody testing to specific antigen after immunization
• screens for:
• what to look for:å

Answer 10

• humoral immunodeficiency
• decrease or absent antibody response to vaccination

Question 11

Testing for PID

• lab test: total hemolytic complement assay
• screens for:
• what to look for:

Answer 11

• complement deficiency
• decrease or absent components in classical pathway

Question 12

Testing for PID

• lab test: nitroblue tetrazolium test
• screens for:
• what to look for:

Answer 12

• phagocytic disorder
• abnormal test result

Question 13

What are the 3 main deficiencies present in B, T, and NK cell development that may lead to SCID’s?

Answer 13

• 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

Question 14

• 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

Answer 14

severe combined immune deficiencies (SCID’s)

Question 15

• 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)

Answer 15

adenosine deaminase (ADA) deficiency

Question 16

• 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)

Answer 16

purine nucleoside phosphorylase (PNP) deficiency

Question 17

• 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)

Answer 17

artermis deficiency

Question 18

• 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)

Answer 18

RAG1/RAG2 deficiency

Question 19

• 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)

Answer 19

Janus kinase 3 (Jak3) deficiency

Question 20

• 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

Answer 20

DiGeorge syndrome (DGS)

Question 21

• 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

Answer 21

agammaglobulinemia

Question 22

• 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

Answer 22

X-linked Btk deficiency

Question 23

• 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

Answer 23

isolated IgG subclass deficiencies

Question 24

• 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

Answer 24

IgA deficiency

Question 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

Answer 25

hyper IgM (HIGM) syndrome

Question 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

Answer 26

transient hypogammaglobulinemia of infancy

Question 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

Answer 27

common variable immune deficiency (CVID)

Question 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)

Answer 28

common γ chain deficiency (γC or IL-2Rγ)

Question 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)

Answer 29

IL-7Rα chain deficiency

Question 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

Answer 30

bare lymphocyte syndrome type 2 (BLS II)

Question 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

Answer 31

MHC class I deficiency

Question 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

Answer 32

CD3 complex deficiencies

Question 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

Answer 33

immunodysregulation, polyendocrinopathy and enteropathy X-linked syndrome (IPEX)

Question 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

Answer 34

autoimmune lymphoproliferative syndrome (ALPS)

Question 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)

Answer 35

Wiskott-Aldrich syndrome (WAS)

Question 36

Mutations resulting in increased susceptibility to nontuberculous mycobacteria have been identified in the genes encoding: (3)

Answer 36

- the IFN-γ receptor - the IL-12 receptor - the p40 subunit of IL-12

Question 37

What happens when there are defects in the IL-12/IFN-γ pathway?

Answer 37

(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

Question 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

Answer 38

Th17 deficiency

Question 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

Answer 39

NK cell deficiency (NKD)

Question 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)

Answer 40

chronic granulomatous disease (CGD)

Question 41

- X-linked recessive genetic disease a/w anemia - lack of substrate for NADPH - more individuals are asymptomatic - manifestation: tendency to form granulomas

Answer 41

G6PD deficiency

Question 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

Answer 42

leukocyte adhesion deficiencies (LAD)

Question 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

Answer 43

Chediak-Higashi syndrome

Question 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

Answer 44

C1 and C4 deficiency (sometimes C2)

Question 45

- deficiency in complement system that results in recurrent sinopulmonary infections - most common complement def in Caucasian pops

Answer 45

C2 deficiency

Question 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

Answer 46

- antibody - humoral ab

Question 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

Answer 47

MAC deficiencies

Question 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

Answer 48

C1-INH deficiency

Question 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

Answer 49

paroxysmal nocturnal hemoglobinuria (PNH)

Question 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)

Answer 50

MyD88 deficiency