Immunodeficiency Flashcards
What are the characteristics of primary/innate immunodeficiency?
Genetic or hereditary
Early onset
X-linked or autosomal recessive
What are the two broad categories of primary immunodeficiency and when are they typically discovered?
6months to 2 years of life
- Defects in Ig’s, complement, or phagocytes leading to encapsulated bacterial infection
- Defects in T cells - opportunistic infections like yeast and chicken pox
Does loss of B cells affect bacterial or viral infections more?
Bacterial - will cause recurrent pneumonia or otitis media
What does SCID cause?
Recurrent, severe infections & failure to thrive
Commonly, oral candidiasis, pneumonia + CMV + pseudomonas infections
What makes up the plurality of SCID cases? What cell populations are most affected?
X-linked
Defect in gamma chain for cytokine receptors, which affects T cells most.
B cells survive but cannot proliferate without T cell help
Why are NK cells also reduced in X-linked SCID?
IL-15 is required for NK cell maturation
What other type of SCID is caused by cytokine signalling problems?
Autosomal recessive - JAK3 tyrosine kinase deficiency. Cannot signal from cytokine receptor
What causes most of the remaining autosomal recessive SCID? Why does this not really affect non-lymphocytes?
Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency
Leads to toxic buildup of purines which deactivates ribonucleotide reductase
Non-lymphocytes have 5’ nucleotidase to help them clear this and salvage DNA.
What is the major treatment of SCID? What are the alternative treatments for X-linked and ADA-PNP?
Hematopoietic stem cell transplantation is common.
X-linked - gene therapy via normal gene for gamma chain
ADA - normal ADA gene inserted via virus (successful).
What is Bruton’s Agammaglobulinema, and the mode of inheritance?
X-linked (XLA)
B cells can’t move on from the pre-B stage because of lack of tyrosine kinase (Btk), which signals to start making light chains following successful heavy chain rearrangement in the Pro-B cell stage
What are the symptoms of XLA and how is it treated?
B cell deficiency leads to persistent bacterial infections including pneumonia, bronchitis, and otitis media once maternal Ab’s fall in serum (around 6 months).
Treated via periodic IV immunoglobulins
What causes congenital thymic aplasia?
DiGeorge syndrome - 22q11 deletion
Failed development of 3rd and 4th pharyngeal pouches, including thymus, parathyroid, and C cells of thyroid
How bad is congenital thymic aplasia?
Variable loss of T cells, many of which will have reduced Ig depending on severity.
T cell zones of lympoid organs are depleted
How can you have a T cell deficiency with normal peripheral T cell numbers? Give one example. (cause, how it presents)
The distribution of T cells is off, and you are missing one class.
I.e. Zap70 tyrosine kinase deficiency leads to absence of CD8 T cells. SCID-like phenotype presenting with lots of opportunistic infections and high incidence of autoimmune diseases
What are the two causes of bare lymphocyte syndrome? Presentation?
- Lack of MHC Class 2 - gene
Failure of CD4+ activation, and CID - Low MHC 1 expression due to TAP1 deficiency
Failure of CD8 T cells, bacterial pneumonia + inflammatory lung disease
What is Hyper IgM syndrome? Inheritance? Presentation?
X-linked, due to CD40L deficiency on T cells. Patients make sufficient IgM but cannot class on B cells to other IgM classes
CD40L also needed for macrophage activation
Presentation: Recurrent pyogenic infections
What is CVID?
Common Variable Immunodeficiency
Low Ig’s due to defective T-cell mediated activation of B cell, leads to recurrent lung infections
What is the most common primary immunodeficiency?
IgA deficiency, rarely symptomatic
Loss of what two enzymes can cause a defect in class switching?
Activation induced cytidine deaminase (AID)
Uracil DNA glycosylase (UNG)
What are LAD1 vs LAD2 vs LAD 3?
Leukocyte adhesion deficiencies
LAD1 - loss of integrins on granulocyte cell surfaces
LAD2 - loss of selectin receptor on cell surfaces
LAD3 - Integrin ligands (ICAM) do not become active
What is the clinical result of all leukocyte adhesion deficiences?
Recurrent bacterial infections due to inadequate granulocyte function
What is Chediak Higashi syndrome?
Defective fusion of phagosome and lysosomes, resulting in susceptibility to staph and strep
Neutropenia and defective microbial killing
What causes chronic granulomatous disease?
Deficiencies in NADPH oxidase or NADH oxidase, which are needed to generate superoxide radicals to kill in phagocytic cells.
Chronic opportunistic infections
What is C1 inhibitor deficiency? What is the one main clinical feature?
C1 inhibitor is an important regulator of complement and related symptoms.
It is needed to stop a pathway for bradykinin production, which is a vasodilator causing edema.
Patients will have hereditary angioedema.
How can complement deficiency present?
Alot like a B cell deficiency -> just a lot of recurrent bacterial infections
What are some causes of secondary / acquired immune deficiencies other than AIDS?
Malnutrition - protein-energy malnutrition can affect cell-mediated
Obesity
Chemotherapy
Immune suppression for organ transplant
How does HIV proliferate when the T cell is activated?
Long terminal repeat zone of virus transcript has a site for NF-kappaB binding (needed for intracellular T cell proliferation). Synthesizes viral components whenever the T cell wants to divide
What is the major spike protein of HIV involved in binding immune cell receptors?
Gp120
What are the two forms of HIV tropism?
- Macrophage-tropic
Gp120 will bind CCR5 and CD4 (less) to ride APCs to lympho nodes - Lymphotropic
Gp120 will preferentially bind CD4 and less-so CXCR4 in T cells once in lymph node
How was a patient “cured” of HIV
Received BM transplant from a donor with CCR5 mutation
What is “seroconversion” in HIV infection?
Initially production of antibody against HIV protein which ends the acute phase and lets the immune system recover
Before this, an HIV antibody test would not detect an HIV infection
What is the most common malignancy during HIV infection (other than the opportunistic infections)?
Kaposi sarcoma
What is the mechanism of AZT (azidothymidine)?
Nucleoside analog which interrupt transcription of viral RNA into viral cDNA
(RT inhibitor)
What is HAART?
Highly active antiretroviral therapy
Combines 3 drugs - at least 2 are direct against Reverse Transcriptase and Protease
What is one big challenge to testing HIV vaccines?
Animals are not susceptible to HIV, best model is SIV
