Chapter 5: Immunodeficiency Syndromes and Acquired Immunodeficiency Syndrome Flashcards
Immune deficiencies can be divided into primary (or congenital) immunodeficiency disorders, and secondary (or acquired) immunodeficiencies. What’s the difference between them?
Primary/congenital immunodeficiency disorders are genetically determined. Secondary/acquired immundeficiency arises from complications of cancer, infections, malnutrition, side effect of immunosuppression, irradiation, or chemotherapy.
What is impaired in primary immunodeficiency diseases?
Mechanisms of innate immunity or adaptive immunity (cellular of humoral).
What is impaired in severe combined immunodeficiency (SCID)?
The development of mature T and/or B lymphocytes and defects in both humoral and cellular immunity.
What is the clinical presentation of severe combined immunodeficiency in infants?
Affected infants present with oral thrush (oral candidiasis), severe diaper rash and failure to thrive. These children are extremely susceptible to recurrent severe infections.
What is a treatment for severe combined immunodeficiency?
Hematopoietic stem cell transplantation.
Approximately half of the cases of severe combined immunodeficiency (SCID)
are X-linked. What is mutated in this type of SCID? What is the effect of this mutation?
The gene that encodes for a γ-chain shared by the receptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-15. The effect of the mutation is most noticeable in IL-7 since it is responsible for stimulating survival and expansion of immature B and T cell precursors.
Another 40% to 50% of SCID cases follow autosomal recessive pattern of inheritance. What is mutated in this type of SCID? What is its normal function?
A gene that encodes for adenosine deaminase (ADA) is mutated, the enzyme is normally involved in purine metabolism.
What is the result of mutated ADA in autosomal recessive SCID?
This results in accumulation of adenosine and deoxyadenosine triphosphate metabolites, which inhibit DNA synthesis
and are toxic to lymphocytes.
For gene therapy against SCID, a normal γc
gene is expressed using a viral vector in HSCs taken from
patients, and the cells are then transplanted back into the
patients. What is a downside of this kind of therapy?
20% of patients who received first-generation viral vector developed T cell acute lymphoblastic leukemia, which highlights the dangers of gene therapy.
What are characteristics of X-linked Agammaglobulinemia or Bruton disease?
Failure of pre-B cells to differentiate into mature B cells and as a result absence of antibodies in the blood.
What gene is mutated in X-linked Agammaglobulinemia? And in what is this gene normally involved?
The gene for Bruton tyrosine kinase (BTK). Normally the gene is involved pre-B-cell signal transduction through signalling via pre-B-cell receptor.
During normal B-cell maturation, immunoglobulin (Ig) heavy chain genes are rearranged first, followed by light chain genes. At each stage, signals are
received from the expressed components of the antigen
receptor that drive maturation to the next stage; these
signals act as quality controls, to ensure that the correct
receptor proteins are being produced. What goes wrong in this proces in X-linked Agammaglobulinemia?
In XLA, B-cell maturation stops after the initial heavy chain rearrangement because of the mutation in the BTK-gene. Because of this the pre-B-cell receptor cannot signal the cells to proceed along the maturation pathway. As a result, Ig light chains are not
produced, and the complete Ig molecule containing heavy
and light chains cannot be assembled and transported to
the cell membrane, although free heavy chains can be
found in the cytoplasm
Just read
Because the BTK gene is on the X
chromosome, the disorder is only seen in males. Sporadic
cases with the same features have been described in
females, possibly due to mutations in other genes that
function in the same pathway
What are laboratory findings in X-linked agammaglobulinemia?
There are no or very few circulating B-cells, no plasma cells and no to very low levels of all antibody classes.
What is the clinical picture of X-linked agammaglobulinemia?
Since the disease is X-linked, it can only be found in males. Recurrent bacterial infections (organisms that are normally opsonized by
antibodies) of the respiratory tract can be indications of an underlying immune defect. Because there are no/few antibodies, individuals with the disease are susceptible to some viral infection, mainly enteroviruses.
What happens when a individual with X-linked agammaglobulinemia gets infected with a enterovirus?
These viruses infect the gastrointestinal tract and from there can disseminate to the nervous system via blood.
What is a no-go for individuals with X-linked agammaglobulinemia?
Immunization with live/attenuated poliovirus (because there’s a risk for paralytic poliomyelitis).
What other microbe is dangerous for individuals with X-linked agammaglobulinemia?
The intestinal protozoan Giardia lamblia, normally this protozoan is resisted by IgA, but in affected individuals it causes persistent infection.
What are characteristics of DiGeorge Syndrome?
This syndrome is caused by a congenital defect in thymic development resulting in deficient T-cell maturation. Because of this T cells are absent in the lymph nodes, spleen and peripheral blood.
To what kind of infections are individuals affected by DiGeorge Syndrome susceptible?
To viral, fungal and protozoal infections. But also to intracellular bacteria.
What is the cause of DiGeorge Syndrome?
A deletion of chromosomal region 22q11. This results in developmental malformation (affecting the third and fourth pharyngeal
pouches), these pouches give rise to the thymus, parathyroid glands, and portions of the face and aortic arch.
What’s the result of the defects in the third and fourth pharyngeal
pouches, structures that give rise to the thymus, parathyroid glands, and portions of the face and aortic arch?
- Thymic and T-cell defects.
- Parathyroid gland hypoplasia, resulting in hypocalcemic tetany
- Midline developmental abnormalities.
What are characteristics of hyper-IgM syndrome?
There’s a normal production (sometimes supranormal) of IgM antibodies. But a decrease in production of IgG, IgA and IgE.
What gene is mostly responsible for development of hyper-IgM syndrome (X-linked form)?
A mutation in the CD40L-gene.
What defect is there in hyper-IgM syndrome?
T cells are unable to activate B cells (and induce isotype switching and affinity maturation). Normally isotype switching and affinity maturation are induced when CD40L on antigen-activated T cells engage with CD40 receptor on B cells (or macrophages/dendritic cells). But since CD40L is mutated, isotype switching and affinity maturation cannot be induced.
Hyper-IgM Syndrome can also be inherited in an autosomal recessive pattern. What defect is present in this type of the disease?
A loss-of-function mutation involving either CD40 or AID-enzyme (DNA-editing enzyme that is required for Ig class switching and affinity maturation).
Why are hyper-IgM syndrome patients presented with recurrent pyogenic infecions?
Because of low levels op opsonizing IgG antibodies.
If CD40L is mutated in hyper-IgM syndrome a patient is also susceptible to which disease caused by which organism?
Pneumonia caused by the intracellular organism Pneumocystis jiroveci.
When can hyper-IgM result in autoimmune hemolytic anemia, thrombocytopenia and neutropenia?
When IgM antibodies react with blood cells.
What is a characteristic of Common Variable Immunodeficiency?
It is a group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all antibody types, but sometimes only IgG.
What is normal and what is absent/very low concentrated in common variable immunodeficiency?
There are normal or nearly normal number of B cells, but absent/very low concentrated plasma cells.
What is a consequence of having normal numbers of B cells but absent plasma cells? What does this say about the pathogenesis of the disease?
B cell areas of the lymphoid tissues tend to be hyperplastic. The enlargement of those areas tell us that B cells can still react to an antigen by proliferating, but do not differentiate into plasma cells.
