What type of genetic mutation is involved in the majority of primary immunodeficiencies?
X-linked. This is because most conditions are caused by recessive genes
What pathogens are people with B cell immunodeficiencies more susceptible to?
Extracellular pathogens, enteric pathogens (because of lack of IgA) and some intracellular microbes (like toxoplasmosis b/c CD40L is necessary for activation of macrophages and is absent in X-linked Hyper-IgM syndrome)
A 5-6 month old boy presents with recurrent infection by extracellular pathogens. The boy’s serum is shown in yellow after reacting with anti-human IgA, IgM and IgG rabbit serum. Control serum is in red. What is most likely causing his condition?
X-linked agammaglobulinemia (XLA). This stems from mutation in Bruton’s tyrosine kinase, which is essential for B-cell maturation. B-cell development is arrested and B-cells do not ever leave the bone marrow.
Where do babies get most of their humoral immunity from in the 1st 6 months of life?
IgG from maternal blood that passed through the placenta.
A 5-6 month old boy presents with recurrent infection by extracellular pathogens. After incubating his serum with anti-human rabbit serum, it is shown that IgG, IgA and IgE are absent from his serum. What is causing his condition?
X-linked Hyper-IgM Syndrome. Normally B-cells produce IgM, then undergo class-switching to produce IgG, IgA and IgE antibodies. In this condition, class-switching does not occur because there is a mutation in the CD40L in CD4+ T-cells and B-cell activation does not occur. Then you’re stuck with lots of IgM.
Which one of the patients shown below has X-linked hyper-IgM syndrome or X-linked agammaglobulinemia?
The one on the left, note the absence of germinal centers.
A 5-6 month old boy presents with recurrent viral, extracellular and intracellular bacterial infections. Labs reveal reduced T cell and NK cells with normal B cell levels.
X-linked SCID. This is a recessive mutation in the common gamma chain that results in defective cytokine receptors for IL-7 and 15. Ineffective IL-7 results in decreased T-cell maturation and ineffective IL-15 results in decreased NK cell maturation. Reduction in T-cells indirectly impairs humoral immunity because there is no T-cell help to stimulate B-cells; hence humoral AND cell-mediated immunity are effected and this is SCID.
What other autosomal recessive disease can cause similar symptoms as X-linked SCID?
JAK3 mutations (essential for cell signaling pathway from cytokine receptors) cause B+T-NK- phenotypes. IL-7Ralpha mutations cause B+T-NK+ phenotypes (because IL-15 alpha chain is still functional).
A mother brings in her child complaining of recurrent infections. Physical exam reveals the facial abnormalities shown below (in the mouth, ears and nose). Labs reveal hypocalcemia. What is causing his condition?
Sporadic deletion of chromosome 22q11.2 causes failure of migration of the 3rd and 4th pharyngeal pouches. This results in no thymus and consequently no T-cells develop. Additionally, the parathyroids, cardiac outflow tract and face are also affected.
What type of mutations result in a B-T-NK+ phenotype?
Those that are involved in somatic recombination of V-D-J joining (especially RAG1/2 which code for DNA recombination and repair enzymes). This process is what normally allows B and T cells to express receptors for various antigens.
Innate immunity mutation that affects cellular adhesion
Leukocyte Adhesion Deficiency. This is an AR mutation in the expression of beta-2 integrins in CD18 (LFA-1) that normally binds ICAM-1 so that cells can migrate to sites of infection and inflammation.
Innate immunity mutation that affects phagocytes. How do you test for this disease?
Chronic granulomatous disease. This is an X-linked mutation in phagocyte oxidase that prevents phagocytes from producing ROS for killing of pathogens. Test with nitroblue tetrazolium dye reduction test (turns blue when it reacts with superoxide)
What would you expect to see on histological analysis of this patient’s bowel?
Note the granulomatous inflammation characteristic of chronic granulomatous disease. This results in steady accumulation of macrophages and T-cells that are trying to overcome infection but are not succeed and lots of granulomatous inflammation ensues.
How do you treat chronic granulomatous disease?
IFN-gamma can enhance superoxide dysfunction in macrophages.
How do you treat B cell deficiencies?
How do you treat SCID?
Bone marrow replacement