Lecture 23: Primary Immunodeficiencies Flashcards
When do primary immunodeficiencies (PIDs) manifest?
w/in first year of life
HX and PE thinking suspected PID?
- Recurrent sinopulm. bacterial infections screen for –>
- Recurrent viral/fungal infections screen for –>
- Recurrent skin absesses/fungal infections screen for–>
- Bacteriemia or meningitis w/ encapsulated bacteria screen for –>
- humoral immunity (B cells and Abs)
- cellular immunity (T cells)
- Phagocyte defect
- Complement deficiency
- What is SCID?
- Typically associated w/ severe T-cell ________.
- What is SCID characterized by?
- A fetus w/ SCID is at risk of abortion due to inability to do what?
Severe Combined Immue Deficiency
- rare, potentially fatal syndrome of diverse genetic causes in which there is a profound deficiency of T-cells w/o or w/o dec. in B cells or NK cells
2. Lymphopenia
3. Severe opportunistic infections (due to pathogens that don’t normally cause infections in ppl w/ normal IS), chronic diarrhea, and FTT
4. reject maternal T cells that cross the placenta –> cause immunological rejection
- What deficiency leads to accumulation of deoxyadenosine which is a toxic for T/B cells?
- ImmunoPT = T-B-NK-
- which causes what Ig’s to be low/absent?
- What type of vaccines should be avoided?
- What is the inheritance pattern?
- Adenosine deaminase (ADA) deficiency
- ADA normally converts deoxyadnosine –> deoxyinosine (not harmful)
- deficient ADA esp. harmful to T cells
- IgG, IgA, and IgM
- All live vaccines
- tx = HSCT (hemolytic stem cell transplantation) - Autosomal recessive
- second most common cause of SCID
1. RAG1/RAG2 deficiency is a rare autosomal recessive disorder that causes impaired V(D)J recomination leading to defective expression of what? (which causes SCID)
- what is the immunophenotype?
- Pt presentation starts in infancy w/ diarrhea, candidiasis and opportunistic infections with what bacteria?
-
Leaky RAG1/RAG2 defects allows for partial fxn of RAG1/RAG2 causing an atypical form of SCID known as?
* hint, sx = severe erythroderma, splenomegaly, eosinophilia, and high IgE - What type of vaccines should be avoided?
- pre-TCR and pre-BCR
- T-B-NK+ –> low/absent IgG, IgA, and IgM
- Pneumocystic jiroveci
- Omenn syndrome
- All live vaccines
- tx = HSCT (hemolytic stem cell transplantation)
- What is the deficiency causing a rare form of autosomal recessive radiosensitive SCID?
* T and B cell # are _____ and NK cell # are ____ - Pts have an increased risk of developing what?
- What is the cause of radiosensitivity?
- What type of vaccine should be avoided?
- When and what does the pt present w/?
-
Artemis deficiency
* absent; normal –> T-B-NK+ –> low/absent IgG, IgA, and IgM - Lymphomas
- Artemis is an enz in VDJ recombo and serves to protect dsDNA breaks, which radiation causes
- All live vaccines
- tx = HSCT (hemolytic stem cell transplantation) - Infancy; diarrhea, cadidiasis, opportunistic infections w/ pneumocystis jiroveci
1. Common γ Chain Deficiency (γc or IL-2Rγ) is the an _____ recessive trait, that is the most _____ form of SCID.
- What is it’s immunoPT and what are the associated Ig levels?
- What cell type is present, however NON-functional?
- X-linked; common
- T-B+NK<strong>-</strong> –> IgM+, but l_ow/absent IgG, IgE, and IgA_
- genes encoding GAMMA-CHAIN are shared by T cell growth factor receptor (IL-2Rγ)
- IL-2Rγ also shared with IL-4, IL-7, IL-9, IL-15, and IL-21
- B cells are present but non functional bc T cells are unable to help
- pt’s present in infancy w/ FTT, severe thrush, opportunitic infections, chronic diarrhea
- Avoid ALL live vaccines
- HSCT used for tx
- IL-7R Alpha Chain Deficiency is an _____ recessive form of SCID.
- What does IL-7 play a key role in?
- What is the immunoPT and the corresponding Ab levels?
- What is used to confirm the dx?
- autosomal
- early T cell development
- T-B+NK<strong>+</strong> (B cell present but not functional)–> IgM+, low/absent IgG, IgE, IgA (still low/absent despite B cell presence due to absence of T cell co-stim. signaling)
- IL-7R Gene sequencing
- pt’s present in infancy w/ classic SCID sx = cadidiasis, chronic diarrhea, pneumocystic jiroveci PNA, severe viral infections
- Avoid ALL live vaccines
- HSCT used for tx
- Deficiency of Jak3 causes a defect in _______ signaling, resulting in SCID.
- What is the immunophenotype?
- What are the Ig levels?
- What is the inheritance pattern?
- IL-2R (IL-2R_α_)
-
T-, B+, NK-
* NK cells activated through IL-15R_α_ - IgM+, low/absent IgG, IgE, and IgA (bc B cells are non functional and not getting T cell help)
- Autosomal recessive
- Avoid ALL live vaccines
- HSCT used for tx
- CD3 complex deficiencies (subunits inlucing ___, ___, ___, ___) can cause SCID.
- What is the immunophenotype?
- How does it present?
- What are the Ig levels?
- What is the inheritance pattern?
- delta, gamma, epsilon, zeta
- T-, B+, NK+
- During infancy with acute T cell lymphopenia, FTT, opportunistic infection and chronic diarrhea
- IgM+, low/absent IgG, IgE, IgA —> Ab responses typically dec.
- Avoid ALL live vaccines
- HSCT used for tx
What type of immunodeficiency comprise approximately half of all 1° immunodeficiencies?
B cell immunodeficiencies
- B cell immunodeficiencies are a group of heterogenous disorders resulting from what?
- Dysfunction of B cells results in imparied ab production and inc. susceptibility to recurrent infections particulalry by what bacteria type?
- Disruption of B cell maturation and fxn
- Encapsulated bacteria
B cell immunodeficiencies comprise half of all PIDs
Primary agammaglobulinemia is most commonly inherited as what?
Early B-cell development is arrested at what stage?
- what does this result in?
- what halts B cell development at this stage? (name the prtn)
X-linked trait
Pre-B cell stage
- circulating B cells are absent or have very low #s
- BTK
- X-linked Btk deficiency is a result of a mutation in what?
- What is the immunophenotype?
- Titers of all serum abs (IgG, IgA, and IgM) are ______.
- What type of vaccine should be avoided?
- Who does this condition effect?
- Tyrosine kinase
* due to a defect in the rearrangement of the Ig heavy chain genes - T+, B-, NK+
- Absent or very low
- All live vaccines
* tx with HSCT - Males
- What is the immunoPT and corresponding Ig levels of ppl w/ IgA deficiency?
- Diagnosis includes pt’s presenting w/ recurrent infections typically with what kind of bacteria?
- Most patients are _____ bc IgM is still able to cross mucosal epithelium and other Abs can make up for the loss of IgA.
- Pts may have serum anti-IgA IgG which is linked to development of non-IgE mediated ________ in response to IV Ig transfusion.
- What are the restrictions for vaccinations?
- T+, B+, NK+ –> NO IgA, but nl IgM, IgE, IgG
- Encapsulated
- asymptomatic
- Anaphalyxis
* bc donor blodo will contain IgA abs –> serum sickness
higher prevanlence in males
- There are none
* symptomatic tx
- Isolated IgG Subclass deficiencies have what type of immunoPT and what are the corresponding Ig levels?
- Are these pt’s usually asymptomatic or symptomatic?
- It can be assoc. w/ recurrent viral/bacterial infections frequently involving what area of body?
- What are the restrictions for vaccinations?
- T+, B+, NK+ –> Decreased [] of 1 or more IgG subclasses, but nl IgM, IgA, IgG
- Asymptomatic
- Respiratory tract
- There aren’t any
* tx symptomatically
- In patients with hyper IgM syndrome (HIGM), they have normal # of _____ B cells, but low #s of _______ B cells.
- What are the two impairments w/in the periphery causing this syndrome?
- What is the immunoPT and what are the corresponding Ab levels?
- peripheral B cells; memory
- Ig class switching and somatic hypermutation
- B+, T+, NK+ –> HIGH IgM, but low IgG, IgE, IgA
- Mutations in what cause HIGM?
- X-linked _____ deficiency (male only) is responsible for 2/3 of all cases.
- Autosomal _____ deficiency (male only) is responsible for 1/3 of all cases.
- What vaccination is not recommended for these patients?
- What is not required for IgM, explaining why they are high and other Ig’s are low?
- CD40 and CD40L (costimulatory signaling from Th cells)
- CD40L
- CD40
- Polio
- Does not require T cell help, ie does not require any signaling for proliferation, affinity maturation, or isotype switching
- In transient hypogammaglobulinemia of infancy, intrinic __ production is delayed for up to 36 months.
* this results in low __, ___, ___, but normal ____. - These infants have inc. susceptibility to what kind of infections?
- When do the majority of these patients [Ig] normalize?
- What vaccine is not recommended?
- Ig production is delayed
- IgA, IgG, IgE, but normal IgM
- immunoPT = B+/-, T+, NK+
- Sinopulmonary infections
- b/w 2-4 years
- Polio
* symptomatic tx
Normally Maternal IgG in infant disappears after 6 mo and intrinsic IgG production usually beings immediately after birth
- T cell immunodeficincies are defined as T cell deficiency w/ <300-500 circulating CD3+ cells –> these pt’s are susceptible to ____ infections and malignancies.
- Clinical manifestations may be indistinguishable from what?
- T-cell repertoire and T cell subpopln’s (including _____ and ____ T cells) are abnormal.
- viral infections
- SCID (bc have functional deficiency of B cells***)
* predominant clinical manifestation is autoimmunity or lymphoid malignacy - Treg and memory
Ig’s and specific Abs maybe variable (primarily IgM, but dec IgA, IgG, and IgE)
- Bare Lymphocyte Syndrome Type 2 (BLS II) is a rare autosomal recessive genetic disorder causing HLA class ___ negative SCID.
- What type of T cells would be deficient?
- Which parts of body would be affected by recurrent infections causing death in early childhood?
- What is the immunoPT? and corresponding Ig
- What vaccines should be avoided?
- Class II
* Mutations are in genes which encode for TFs taht nlly reg. expression of MHC II genes - CD4+ T cells
- respiratory, GI, and urinary tract infections
- T+, B+, NK- ; –> normal IgM, IgG, IgE, IgA
* variable hypogammaglobulinanemia (mainly IgA and IgG2) - All viral live
* HSCT is curative
- MHC Class I deficiency is caused by a mutation in what mlcls that transport peptides to the ER?
- What T cell would be deficient?
* this deficiency would result in what type of reccuring infections? - What vaccines should be avoided?
- What is the immunophenotype and corresponding Ig levels?
- TAP1 and TAP2
- Ag processing to peptides in proteosome
- TAP1 transports them to the ER where they can bind MHC Class 1
- CD8+ –> viral infections
- All viral live
- T+, B+, NK-
- normal Ab production (nl IgM, IgG, IgE, IgA)
- normal DTH (delayed type hypersensitivity)
- What syndrome is a classic example of T-cell deficiency that results from a microdeletion of 22q11.2 region containing more than 35 genes?
- What is the classic triad that this syndrome causes?
- What type of immunity would be intact for most pt’s?
- What type of vaccine should be avoided?
- What is the immunoPT and corresponding Ig levels?
1. DiGeorge Syndrome (DGS)
- Cardiac anomalies, hypocalcemia, and hypoplastic thymus (which leads to T cell immune dysfunction)
* Patients often suffere from frequent URI’s. - Humoral (bc portion of CD4 remaining cells will still have B cells)
- All viral live
- T-, B+, NK+ –> nl IgM, IgE, IgG, IgA
treat symptomatically or thymus transplantation