ICL 7.2: Immunodeficiencies Flashcards
what are the clinical features of x-linked hyper-IgM syndrome?
x-linked recessive
blockade of helper T cell-dependent activation of naïve B cells
no isotype switching
recurrent infection
what are the 5 immune defense mechanisms against infectious microbes?
- antibody-mediated immune defense
- T cell-mediated immune defense
- NK cell-mediated immune defense
- phagocyte-mediated immune defense
- complement-mediated immune defense
how are extracellular pathogens cleared by the immune system?
lots of bacteria replicate in extracellular spaces = extracellular pathogen
they can be cleared by antibodies, phagocytes, complement, and antimicrobial peptides
how are intracellular pathogens cleared by the immune system?
certain bacteria and all viruses must invade host cells to replicate = intracellular pathogens
which cells kill host cells infected with cytoplasmic pathogens?
CD8 cytotoxic T cells
NK cells
which cells promote the killing of intravesicular pathogens in phagocytes?
CD4 TH1 cells
NK cells
how can pathogens stick around in your body without being destroyed by the immune system?
- evade surveillance by altering their antigens
- persist in the hosts in a state known as latency
- become undetectable by the host immune system by down-regulating host receptors
- actively destroy the immune defense system by producing inhibitors of immunologically important host factors
what are the two categories of immunodeficiency diseases?
- primary immunodeficiency diseases (inherited)
2. secondary immunodeficiency diseases (acquired)
what are primary immunodeficiency diseases?
mutations of genes involved in host immune system
they are genetically encoded
what are secondary immunodeficiency diseases?
they are acquired as a consequence of other disease, caused by environmental factors, or manifested as an adverse effect of medical intervention
they’re caused by an infectious agent, cancer, radiation, starvation, stress etc.
ex. AIDS
what does SCID stand for?
x-linked severe combined immunodeficiency
what causes SCID?
it’s caused by a mutation in the common gamma chain of interleukin receptors on T cells – all these IL receptors have the same gamma chain in their receptor
if there’s a mutation in the receptor it’ll cause issues with the IL signaling because they won’t be able to respond to any cytokines
which IL receptors are common gamma chain receptors?
IL-2R
IL4R
IL-7R
IL-9R
IL-15R
IL-21R
what are the consequences of SCID?
gamma chain of IL receptors is mutated
IL-2, IL-7, and IL-15 play crucial roles in the development, growth, and survival of T cells so people with common γ-chain gene mutations have almost complete depletion of T cells!
then, since T cells are required for activation of B cells recognizing T cell-dependent antigens, the X-SCID patients also fail to develop antibody-mediated immune responses to such antigens
NK cell development also require IL-2 and IL-15 too so there is decreased number of NK cells
- no T cells,
- reduced NK cells
- reduced B cell function
- severe immunodeficiency
how are B cells effected in SCID?
B cell number remains normal
BUT their function is impaired because T cell development is impaired and without T cells, B cells don’t get activated
what clinical presentation would make you think someone has SCID?
if you have given someone a measles vaccine but then a month later they come in with the measles this could be due to SCID!
it’s showing you that they didn’t have a memory response against this antigen
what are ADA and PNP deficiency?
ADA and PNP are enzymes responsible for nucleotide catabolism (breakdown)
so if you don’t have these enzymes or mutations in them, you get buildup of adenosine & guanosine nucleotides which can be toxic in rapidly dividing cell types like T and B cells that are undergoing an immune response!
what are the effects of ADA and PNP deficiency?
there’s a mutation in the ADA or PNP gene that leads to a buildup of nucleotide metabolites that can be toxic in T and B cells
so then you have decreased T and B cells which can lead to SCID!
what clinical finding do you see in patients with ADA or PNP deficiency?
infants with ADA or PNP deficiency show under-developed thymus as detectable in chest X-ray
what is a RAG gene mutation?
VDJ recombination of the immunoglobulin gene and the T cell receptor gene requires two enzymes encoded by the RAG1 and RAG2 genes
so you can have a RAG1 or RAG2 mutation that lead to abnormal RAG function or a totally non-functional RAG protein
RAG genes are important in B and T cell receptor generation so if you have a mutation in RAG1/RAG2, you can get either inactive receptors or poorly functional receptors
what are the effects of a RAG gene mutation that leads to an abnormally functioning T cell receptor?
- GVHD-like phenotype
- eosinophilia
- elevated IgE
- Omenn syndrome
what are the effects of a RAG gene mutation that leads to a non-functional T cell receptor?
SCID!
what is Omenn syndrome?
can be result of abnormal RAG function
leads to:
- recurrent infections
- GVHD-like features: red rash, protracted diarrhea, and lymph node swelling
- eosinophilia with elevated IgE
what do RAG1 and RAG2 do?
RAG 1 and RAG2 protein complexes bind to 12 and 23 bp spaced recombination signal sequences (RSSs) –> the RAG1 and RAG2 protein complexes bind to each other, bringing together the segments to be joined
they’re genes located at the ends of VDJ genes and shuffle and rejoin VDJ = VDJ recombination
they recognize RSS and cleave double stranded RNA between the Ag receptor and RSS
