HTHSCI 3I03 Lecture Notes - Lecture 4: Immunodeficiency, Lymphocytopenia, Virome

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CASE STUDY 1: Importance of Neutrophils
- Derek has Kostmann Syndrome: deficiency in neutrophils
o Bone marrow fails to produce neutrophils to fight infections, so prone to life-threatening infection
Severe Congenital Neutropenia (SCN)
- Autosomal dominant (sometimes, or recessive) inheritance
- Caused by different mutations typically in ELANE gene protein in a neutrophil granule used to fight infections, which
affects the myeloid lineage
o Results: arrest in BM = accumulation of myeloid precursor, so cannot produce mature neutrophils
- As the disease progresses, the individual develops more mutations => MDS or AML
Diagnosis
- Consistently low neutrophil count right from birth: < 500/mm3
Why are neutrophils so critical to fighting infection?
Neutrophils are the first innate cell to be recruited to the site of local infection via granules in phagocytosis and netosis. So if
neutrophil cannot clear local bacterial infection, it can cause the bacteria to spread => systemic infection and ultimately lead to
sepsis.
What immune response occurs in sepsis and why is it often fatal?
PAMPs and DAMPs are recognized by its binding to PRRs resulting in local inflammation as immune cells are travel to the site of of
infection to target the infection. In sepsis, the body’s immune checks fail, so instead of the inflammatory forces disappearing, they
spread beyond the infected region. So PAMP and DAMP recognition throughout the body causes the immune system to overreact,
resulting in systemic inflammation. Massive dilation of blood vessels making them leaky and allowing for blood contents to leak out
and create a gel throughout the body organ damage and death. To compensate, it stops secreting cytokines which stops immune
cells from functioning => dysfunctional immune system. So that means that the human cannot respond to infections in the future).
Treatment
1. How can G-CSF be used to treat SCN?
a. Granulocyte-colony stimulation factor. A glycoprotein that stimulates neutrophil, eosinophil and basophil
differentiation. So provide the cytokine that will drive these immune cells that are stuck in the pre-differentiating
phase => to differentiate and form neutrophils
b. Not always effective: condition is characterized by a lot of mutation
2. Bone marrow transplant
a. Stem cells are collected from the donor and processed to purify and concentrate the stem cells. Patient will
undergo high dose chemotherapy/radiation therapy to deplete their stem and progenitor cell populations. Donor
cells are reinfused into the recipient.
How could a BM transplant help Derek?
Since his stem cells have so many mutations, they cannot differentiate, and thus, are dysfunctional. Introducing functional stem cells
(without mutations) will allow proper differentiation and therefore development of neutrophils.
What does it mean when they refer to his brother as a perfect match?
- T-cells undergo negative selection so they recognize and don’t attack self-antigens. Therefore, introducing different stem
cells can warrant an immune response.
- MHC (in mice) or HLA (in humans; human leukocyte antigen): Matching between A, B, C, DARB1 and DQ
o ABC + DARB1 x / 8 match
o ABC + DARB1 + DQ x / 10 match
CASE STUDY 2: Immune System and Acne
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