Flashcards in Immunodeficiencies Deck (52)
Is immunodeficiency, once acquired a permanent thing?
• Not necessarily. Some conditions exist where there are temporary immunodeficiencies
• Hypogammaglobulinemia of infancy
• Chemotherapy treatment leading to suppression of immune system
What are the two basic types of immunodeficiency?
• Primary and secondary
• Congenital (primary) and acquired (secondary)
What other types of cells, not necessarily from the bone marrow, but important for T-lymphocyte development are messed up in DiGeorge syndrome and why?
• DiGeorge syndrome is a congenital disease where certain amaeboid cells (endoderm and ectoderm derived) from the pharangeal arches in the embryo do not establish the support stroma of the thymus
• They also don't establish the thyroid or parathyroid glands for that matter since the same migratory cells are responsible for the establishment of each of these organs
What does primary immunodeficiency mean?
• There are mutations in genes required for normal development of parts of the immune system
• These mutations usually lead to diminished function or loss of function
What is the development outline for a T-lymphocyte?
Starts out in the bone marrow as an hematapoietic stem cell
• Matures just a little into the Lymphocytic stem cell
• Reaches pre-T-cell before exiting the bone marrow en route to the thymus for positive/negative selection
Many genetic mutations that result in immunodeficiency end up presenting in patients less like a black/white disease and more like a spectrum or continuum of disease…what's that an example of?
• Variable penetrance
Besides the adaptive immune cells themselves, what problems in the whole pathway can lead to immunodeficiency?
• Anywhere in the innate/inflammatory/adaptive immune response
• If neutrophils are not functioning, certain infections are tough to eliminate
• If phagocytosis is knocked out, antigen presentation can get tricky and the adaptive arm never kicks in
What is the disease where a patient has a block super early in the production of lymphocytes, like in the bone marrow before generation of even the lymphoid stem cell?
• SCID, severe combined immunodeficiency disease, the worst of the bunch
• No thymus, no B or T cells, no adaptive immunity, death after a year
What is the deal with SCID?
• A group of genetic disorders that result in the same phenotype - lymphocytopenia (or is it lymphopenia?)
• Most (50% ish) are X-linked recessive
What's the deal with SCID-X1?
• This is the most common genetic abnormality that drives development of SCID
• Gene for the gamma chain that forms part of the receptors for IL-2 and other cytokines necessary for lymphoid development, or their signaling pathways
What would happen if the Pre-B and B cell numbers are fine, but for some reason they are difficult to drive into full maturation and class switching?
• This is the case in Common Variable Immunodeficiency (CVID)
• Group of 20 or so conditions resulting in same phenotype
• Main problem is increased bacterial infection
• Patients have a higher risk of lymphoma, enteropathy, autoimmunity
What would happen if you knocked out the gamma chain involved in IL-2 receptor - IL-2 binding?
• This is the exact problem in SCID-X1, so you would get SCID, and have no development of T or B cells
CD40-L is on what cell and has what other name?
• The other name is CD154 and it is the T-cell surface molecule that helps drive B-cell class switching
• When you see it think Tfh and B-cell maturation
If the defect causing SCID isn't X-linked recessive, then what is it likely?
• 1/2 the cases are X-linked recessive, the other 1/2 are autosomal recessive
• The autosomal recessive disorders are caused mostly by ADA deficiency
CD40 is on the surface of what cell?
• B-cell. Used in class switching
What happens in ADA deficiency?
• ADA = adenosine deaminase
• Adenosine accumulates in all cells but it selectively inhibits the development of lymphocytes
What molecules need be affected in X-linked hyperIgM syndrome?
• CD40 (B-cell) and CD40L (or CD154…same thing) in the T-cell
What disease is rare globally but for some reason unfortunately common in Navajo and Apache children?
• SCID due to V(D)J recombination deficits
What might be the result of a problem in the CD40;CD40-L binding of Tfh and B-cells?
• This interaction of CD40 (B-cell surface molecule) and CD40-L/CD154 (T-cell ligand for CD40) is responsible for driving a B cell to class switch from IgM to another antibody
• Thus, if the driving force of class switching is defective there will be no class switching.
• X-linked hyperIgM syndrome is the likely result
What might be the result of a block between the pre-B-cell stage and the mature B cell stage?
• X-linked (Bruton) Agammaglobulinemia is a great example of this problem
• Patients have less than 10% of normal IgG and they don't have IgA or IgM
• Btk is a protein tyrosine kinase that is messed up in this disease
What is the normal expression pattern of btk?
• A tyrosine kinase made in pre-B cells that are maturing into naïve and mature B-cells.
• Defective in Bruton Agammaglobulinemia (X-linked)
What is the main reason we don't use oral polio vaccine in America?
• Bruton's Aggamaglobulinemia children. They have no They have no IgA and polio vaccine can cause problems because of it's abnormally easy entry in the mucosa of these children
What is meant by "the thymus is a two-component organ"?
• There is a lymphoid component from the bone marrow
• There is also a stroma component that comes from the ameoboid cells in the pharangeal arches (endoderm and ectoderm)
What would happen if the stroma component of the thymus never got developed because of a genetic abnormality that altered the function of the ectoderm and endoderm of the pharangeal arches?
• This is the case in DiGeorge syndrome
• Even if the T-lymphocyte precursors get to the thymus like normal, there is not the infrastructure available to develop them further
• The end result is absent T-cells but fine numbers of B-cells
What are the three paricularly common immunospressive viral infections?
What are the common problems in wiskott-aldrich syndrome?
• Platelet and B-cell deficiency
• Recurrent varied bacterial infections
• X-linked disease
What's the deal with DiGeorge syndrome?
• Large deletion on chromosome 22
• Absent T-cells but fine number of B-cells
• B-cells can't be fully matured b/c no T-cells
• Main problem is no stromal component of the thymus
• Parathyroid glands also affected for the same root reason
○ Results in hypocalcemic seizures
What is one primary immunodeficiency that is just as known for it's predisposition to tumor development?
• Ataxia telangiectasia
• Ataxia = staggering and lack of coordinated movement
• Telangiectasia = abnormally dilated blood vessels (think old person vessels on the tip of the nose)
• Presents with sinus infections and pneumonia because of a T and B cell deficiency (not absolute)
• The tumor component is a DNA repair enzyme malfunction
T-cell deficiencies are particularly linked to what two types of infection?
• Intracellular and fungal infection
• Candida albicans (fungal)
• Pneumocystis jirovecii (intracelluar bacterium)