2.1.1 Immunodeficiencies Flashcards
Distinguish b/t primary and secondary immunodeficiencies.
Primary (congenital)
Secondary (acquired): infections, nutritional abnormalities, medical treatments
X-linked SCID is what type of primary immunodeficiency?
Defect in lymphocyte maturation.
Only males affected.
Mutations in gene encoding gammaC signaling subunit.
What types of cells are absent in X-linked SCID?
T cells and NK cells
Which cytokines require gammaC for signaling?
IL-2, 4, 7, 9, 15, 21
What type of cell development is blocked in X-linked SCID?
T cells due to lack of IL-7
The NK cell deficiency of X-Linked SCID is a result of which cytokine receptor missing its gammaC subunit?
IL-15R
Would you expect antibody responses to be normal in an X-linked SCID patient?
No, most Ab’s would be IgM in this patient.
Describe nine characteristics that would implicate immunodeficiencies as an underlying disease.
- 8 or more new ear infections in 1 y.
- 2 or more serious sinus infections within 1 y.
- 2 or more months on antibiotics w/ little effect
- 2 or more pneumonias within 1 y.
- Failure of an infant to gain weight or grow normally (thrive)
- Recurrent, deep skin or organ abscesses
- Persistent thrush in mouth or elsewhere on skin, after age 1
- Need for intravemenous antibiotics to clear infections
- 2 or more deep-seated infections
- A family history of primary immunodeficiency
In X-Linked SCID, why is there an NK cell deficiency?
The gamma chain of the IL-15R is absent/non-functional leading to lack of stimulation
What are the 3 sites of mutations in autosomal SCID?
- Purine salvage pathway [Adenosine deaminase (ADA) or Purine nucleoside phosphorylase (PNP)]
- Mutation in JAK3 (required for gamma c signaling)
- Mutation in RAG1/2
There are two different types of RAG1/2 disorders in autosomal SCID. Which is associated w/ reduced RAG protein expression?
Omenn Syndrome
(There is no special name for the complete loss of RAG1/2)
Which cell types are missing in a patient lacking RAG1 expression?
T cells and B cells
In addition to multiple infections, what is a common clinical manifestation in Omenn syndrome?
a) Allergy
b) Autoimmunity
c) Leukemia
d) Solid organ cancers
b) Autoimmunity
What mutation is responsible for X-linked agammaglobulinemia? What would be lost as a result?
BTK (bruton tyrosine kinase); Lose: mature B cells and serum Igs
Most states, Kansas is in the process of doing so, have implemented screening for newborn SCID. What test is used?
T cell receptor excision circle (TREC) assay
DiGeorge Syndrome is associated with what genetic variation?
22q11.2 deletion syndrome
What are the clinical manifestations of DiGeorge Syndrome?
Heart defects, cleft palate, delayed development, incomplete development of thymus (low T cell #s)
Catch 22
What is the mutation responisble for X-linked Hyper IgM Syndrome? What doesn’t occur as a result?
CD40L; No Ab class switching
What mutation is responsible for autosomal Hyper IgM Syndrome? What doesn’t occur as a result?
Activation-induced deaminase (AID); No Ab class switching nor somatic hypermutation
What is the most common primary immunodeficiency? (hint: the underlying defect is usually unknown)
Selective IgA Deficiency
What are all the A-words associated with Selective IgA Deficiency?
Majority Asymptomatic
Airway and GI infections
Autoimmune dz
Atopy
Anaphylaxis to IgA-containing products
Which of the following do you think could be clinical symptoms of IgA-Deficiency
a) Arthritis
b) Inflammatory Bowel Dz
c) Multiple schlerosis
d) Psoriasis
b) Inflammatory Bowel Dz
Which of the following is the best treatment option for IgA-deficiency?
a) antibiotics
b) IgA transfusions
c) IL-4
d) IVIG
a) antibiotics
Which serum levels are reduced in Common Variable Immunodeficiency (CVID)?
IgG, IgA, IgM
What are some co-morbidities associated with CVID?
recurrent infections, autoimmunity, and lymphomas
What are some Defective T Cell Activation dz’s?
Bare lymphocyte syndrome, selective T cell deficiencies (Th1, Th2, Th17, Tfh)
Give three deficiencies that would lead to Th1 deficiencies? What type of infections would be these patients be succeptible to?
IFN-gammaR1, IL12betaR1, IL-12 deficiency
Atypical mycobacterial infections
What would would be lacking in a patient with Th17 deficiency? Vunerable to what type of infection?
IL-17; Chronic Candida albicans and S. aureas
What is mutated in Wiskott-Aldrich Syndrome (WAS)? What are the three dysfunctions associated with WAS?
WASP on the X chromosome;
T cell defective, platelet dysfunction, dyfunction in motility/cytotoxic function of most immune cells
What is mutated in Ataxia-telangiectasia (ATM)? What abnormalities are associated with ATM? Which lymphocytes are affected?
ATM: DNA repair enzyme, defect in VDJ recombination
Ataxia: gait abnormalities, Telangiectasia: vascular malformations
B and T cells affected
What are five primary innate immunodeficiencies?
Chronic granulomatous dz (CGD)
Leukocyte adhesion deficiency (LAD)
Complement protein deficiencies
Chediak-Higashi syndrome
TLR signaling
What leads to the two types of LAD:
LAD-1?
LAD-2,3?
LAD-1: Absence of CD18 (LFA-1, CR3, CR4)
LAD-2,3: Defects in selectin ligand (Siayl Lewis)
What are some potential sources of deficiencies in complement?
C1, C2, C4
Factor I or H
Chediak-Higashi Syndrome: which cells are affected? Which two processes are affected? Type of associated infections?
Neutrophils and macrophages
Defects in lysosomal vesicle formation and trafficking
Frequent and severe bacterial infections
What are some potential causes of secondary immunodeficiencies?
HIV, Cancer treatment (chemo, radiation), Immunosuppressive drugs, Malnutrition (protein)
Identify the cytokines that use the common gamma chain and describe their common signaling pathway.
IL-2, 4, 7, 9, 15, 21
Common signaling pathway: JAK-1, 3
