Immunodeficiencies Flashcards
What is the difference between priamry and secondary immunodeficiencies
- Primary is congenital
- Secondary is acquired through infections, nutritional abnormalities, and medical treatments
What is X-linked SCID?
Primary Immunodefiency, where there is a defect in lymphocyte maturation.
- only males affected.
- mutation in gene coding gamma C signaling subunit (normally on IL receptors)
- there is an absence of T cells and NK cells
Which cytokines require gamma C for signaling?
IL
In X-linked SCID, what is the cause for very few or no T cells?
Lack of production of IL-7 due to mutation in gamma C subunit of IL-7 receptor (normally leads to JAK/STAT pathway)
The NK cell deficiency of X-linked SCID is a result of which cytokine receptor missing its gammaC subunit?
IL-15 receptor which would normally be responding to IL-15 and type I IFNs, activating NK cells which will secrete IFN gamma and help control viral infection/replication
Would you expect antibody response to be normal in an X-linked SCID patient?
No, antibody production of B-cells relies on classswitching and activation by T-cells, since there is no T-cell activation telling the what antibody to be produced, you would not get normal levels of antibodies and most of them would be IgM
What are the nine characterisitcs that would implicate immunodeficiencies as an underlying disease?
- 8 or more new ear infections in 1 year
- 2 or more serious sinus infections in 1 year
- 2 or more months on antibiotics w/ little effect
- Two or more pneumonias within 1 year.
- failure of an infant to gain weight or grow normally.
- recurrent, deep skin or organ abscesses
- persistent thrush in mouth or elsewhere on skin, after age 1
- Need for IV antibiotics to clear infections
- Two or more deep-seated infections
- A family history of primary immunodeficiency.
What are the 3 sites of mutations in Autosomal SCID?
- Mutation in the purine salvage pathway (Adenosine Deaminase ADA most common) or mutation in purine nucleoside phorylase (PNP)
-leads to build up of purine metabolites that are toxic to T cells causing them to die
- Mutation in JAK3 (required for gamma c signaling)
- Mutation in RAG1/2 (a mutation in RAG genes that result in reduced RAG protein expression is Omenn Syndrome)
What would a reduced expression of RAG proteins lead to?
Omenn Syndrome is reduced expression of RAG genes
Which cell types are missing in a patient lacking RAG1 expression?
They would be missing T cells and B cells because RAG1 expression is responsible for production of TCRs and BCRs
In addition to multiple infections, what is a common clinical manifestation in Omenn Syndrome?
Autoimmunity (reasoning is not completely understood)
What is the underlying mutation responsible for X-linked aggamglobulinemia? What would be lost as a result?
Mutation in BTK (Bruton Tyrosine Kinase) leads to loss of mature B cells, loss of serum Igs, and Autoimmunity
Most states, Kansas is in the process of doing so, have implemented screening for newborn SCIDs. What test is used?
TREC assay (T cell receptor excision circle)
What would be the clinical findings for a SCID?
- decreaed TRECs
- absence of Thymic shadow on chest x-ray]
- absence of germinal centers on lymph node biopsy
- and absence of T cells on flow cytometry
What are the presentation and treatment for SCID?
failure to thrive, chronic diarrhea, thrush, recurrent infections
-treatment is bone marrow transplant (no concern for rejection in this case because there is no production of antibodies)
DiGeorge Syndrome is associated with what genetic varriation?
22q11.2 deletion, leads to developmental failure of 3rd and 4th pharyngeal pouches and thus absent thymus and parathyroids
What are the clinical manifestations of DiGeorge Syndrome?
Deletion on chromosome 22
- heart defects, cleft palate, delayed development
- also hypocalcemia due to lack of parathyroids
- catch 22
What is the underlying mutation responsible for X-linked Hyper IgM syndrome? What doesn’t occur as a result?
Mutation in CD40L (on CD4 cells) that leads to no antibody class switching, hence all you have is IgM
What is the underlying cause of Autosomal Hyper IgM syndrome?
Mutation in activation-induced deaminase (AID) leads to no antibody class switching and no hyper mutation
What are the clinical finding of Hyper Ig-M syndromes (both X-linked and autosomal)
-normal or increased IgM
-decreased IgG, IgA, and IgE
-because no class switching
What is the most common primary immunodeficiency?
Selective IgA deficiency
- 1 in 700
- often no clinical problems and underlying defect is usually unknown
What is the clinical presentation of Selective IgA syndrome, what about the clinical findings?
Thinks A’s
Major Asymptomatic, Airway and GI infections (IgA is mucosal), Autoimmune disease, Atopy (allergic hypersensitivites), Anaphylaxis to IgA-containing products.
=findings are decreases IgA with normal levels of IgG and IgM
What do you think could be a clinical symptom of IgA- deficiency?
Inflammatory bowel Disease (mucosal)
What is the best treatment option for IgA- deficiency and why?
Treat with antibiotics. IgA transfusions is not an option becasue it would cause hypersensitivity
Which serum levels are reduced in Common Variable Immunodeficiency?
IgG, IgA, and IgM
What are some co-morbidities associated with CVID?
Recurrent infections, autoimmunity, and lymphomas
- CVID is a hetergenous group of disorders
- poor antibody responses to infections
- multiple causes, 90% are unknown
- major one is defect in genes involved with B-cell survival, maturation, activation, and differentiation
What are some defective T cell activation diseases?
Bare Lymphocyte syndrome, selective T cell deficiencies (Th1, Th2, Th17, Tfh)
What can cause Th1 deficiencies? What type of infections would these patients be susceptible to?
IFN gamma receptor 1, IL-12 beta receptor 1, or IL-12 deficiencies
-most susceptible to atypical myobacterial infections
Tell me everything about WAS?
Wiskott-aldrich Syndrome
- due to a mutation is Wiskott-Aldrich Syndrome protein (WASP) on the X-chromosome
- only expressed in leukocytes and megakaryocytes
- involved in reogranicazation of actin cytoskeletin
- T cell function is defective
- platelete dysfunction
- dysfunction in motility and cyototoxic function of most immune cells
WATER Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent infections
-low to normal IgG, and IgM, but increased IgE and IgA, and fewer and smaller platelets
What are Th17 deficincies caused by and prone to?
IL-17 deficiencies, prone to chronic Candida Albicans and S. Aureas
What is ATM?
Ataxia-Telangiectasia
-mutation in ATM gene –> failure DNA repair and defect in VDJ recombination
Ataxia= gait abnormalities
Telangiectasia = vascular malformations
-low lymphocyte numbers (B and T cells effected)
What are some innate immunodeficiencies?
Chronic Granulomatous Disease 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, or selectin ligand expression
What are some potential soucres of deficiencies in complement?
C1, C2, C4, Factor I or H
-associated with bacterial infections and autoimmunity
In 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,
frequenct and severe bacterial infections
