Primary Immunodeficiencies Flashcards
If someone presents with persistent extracellular bacteria/fungi/protozoa infections, what parts of their immune system are most likely defunct?
B cells/Ig or CD4+ T cells of the adaptive immune system.
Could also be complement from the innate system
If someone presents with intracellular bacteria/fungi/protozoa often, what part of their immune system is having issues?
CD4+ T cells (TH1 particularly)
If someone keeps getting viruses, what part of their immune system do we worry about?
CD8+ (CTL) T cells of the adaptive and Type I IFN/NK cells of the innate system, but mostly the CD8+ is what we worry about
What allele do many immunodeficiencies exist on?
X chromosome.
Obviously usually a recessive defect
Lack of B cells = extracellular pathogens.
What is the main route of destruction of these guys?
Usually caused by issues with B cell development
Two big B cell immunodeficiencies
XLA - X linked Agammaglobulinemia
X-Linked Hyper-IgM Syndrome
What the hell is going on with XLA?
Mutation is the gene for Bruton’s tyrosine kinase Xq21
Required for B cell development in bone marrow.
Discuss the XLA penotype
5-6 months of age it develops
This is because in utero the baby is getting IgG from mom. The baby does not start making its own IgM until month 5 or 6.
We will see reduced levels of all Ig’s.
What is happening with X-Linked Hyper-IgM Syndrome?
IgG, IgA and IgE are absent from serum with a compensatory increase in IgM
Recall that B cells always make IgM when exposed to antigen. There is no class switching in this condition to IgG, A, or E due to a mutation in the CD40 ligand (CD40L) gene at Xq26 on CD4 T Helper cells, which can now no longer cause the class switching of B cells.
What will we see in the lymph nodes for someone who has Hyper-IgM?
Devoid of germinal centers
Presentation of Hyper-IgM
Increased susceptibility to extracellular bacterial infections
and enteric infections since we don’t have IgA.
Also, intracellular microbes! Recall that macrophages ALSO use CD40L, so we can’t digest things in the innate pathway as well (we can still use IFN-y to turn on macrophages)!
How will severe combined immunodeficiency patients present?
- Early with recurrent infections of a wide variety
- Fatal, need bone marrow transplant since B and T cells are gone (or just T cells since they turn on B cells)
What are the two main causes of the SCID phenotype?
- X linked SCID
- DiGeorge Syndrome
What the hell is going on with X-linked SCID?
Recessive mutation in the common y chain gene on Xq13.
This is the third chain needed to make the IL-2, 4, 7, 9, and 15 receptors. The most dangerous are 7 and 15 receptors being down
IL-7 - Can’t mature T cells
IL-15 - Can’t make NK cells
We see relatively normal B cell counts, but humoral immunity is shit since we can’t stimulate them
What causes the same phenotype as X-linked SCID?
JAK3 (19p13)
JAK3 is what the common y chain is activating. So same story.
IL-7Ra (5p13)
the a chain is the other partof the IL-7 receptor, so without it, no JAK3 activation = same story (although we will see normal NK cell levels since IL-15 is good to go)
Recall: What is going on with DiGeorge Syndrome?
Deletion of 22q11.2 (loss of T-box 1 and TUPLE1) (usually sporadic, one of the most common) causing issues with development of 3rd and 4th pharyngeal pouches during 12th week of gestation. Defects: - Thymus - Parathyroid glands - Cardiac outflow tract - Facial tissues
Presentation of Di George
Thymus gone = T cells reduced or gone
Parathyroid glands gone = Hypocalcemia presenting as tetany or seizures
Facial tissues screwed up = micrognathia, mis-shaped mouth, abnormal low set ears, palatal clefting, bulbous nose and other things that remind you of chelsea.
What other mutations will case SCID-like phenotypes, specifically B-T-NK+ ones?
Mutations in DNA recombination and repair enzymes (RAG1, RAG2, Artemis)
What is going on with Leukocyte Adhesion Deficiency Type 1?
Exactly like the name suggests, we have an issue with part of an adhesion receptor on WBCs.
In this case, its the LFA-1 receptor that binds the ICAM-1 ligand on endothelial cells. It is absent or deficient in its B2 component due to an autosomal 21q mutation
Patient will present with recurrent bacterial and fungal infections because the granulocytes can’t get out of circulation into the tissues
What immune defect do we see with chronic granulomatous disease?
Phagocyte abnormalities, very rare, only 1:1,000,000 births.
We see recurrent bacterial and fungal infections, common with innate immunity defects
In chronic granulomatous disease, what precisely is affected?
Mutations in components of the phagocyte oxidase, particularly cytochrome b558/p91-phox complex (Xp21 mutation)
Without the peroxidase, the phagolysosome won’t actually kill the microbe because free radicals can’t be made
How do we test phagocyte oxidase function?
Nitroblue tetrazolium dye reduction test. Turns the solution blue if the peroxidase works
What happens on the cellular level is CGD when the peroxidase is not actually killing stuff?
Chronic activation of T cells and macrophages so we see a lot of inflammation, IL-12, interferon-y, activated macrophages and T cells all over the place
How do we treat CGD? You’re gonna love this
Believe it or not…IFN-y therapy. More IFN-y actually enhances oxidase transcription to restore superoxide production to 10% of normal
