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
what is Bloom’s Syndrome?
it’s a mutation in DNA helicase which is responsible for unzipping DNA so that you can do DNA replication
without DNA helicase, you have reduced numbers of T cells, cancer, low antibody levels, etc.
what are the characteristics of Bloom Syndrome?
failure to repair DNA damage and abnormal cell cycle progression leads to:
- reduced T cell number
- reduced antiobdy levels
- premature aging
- cancer
- photosensticity
what is ataxia telangiectasia?
it’s due to a mutation in the ATM gene that is a signaling molecule in the cellular response to DNA damage
ATM protein activates p53 which is involved in DNA repair and regulating the cell cycle
failure to repair DNA damage leads to abnormal cell cycle progression and causes:
- reduced T cell number
- premature agining
- cancer
- neurodegeneration (which leads to ataxia)
- telangiectasia
what is Wiskott-Aldrich Syndrome inheritance?
x-linked
what causes Wiskott-Aldrich Syndrome?
mutation in the WASP protein which is involved in reorganization of actin cytoskeleton of T cells
WASP plays important roles in T cell receptor-dependent activation of T cells
WASP is only expressed in leukocytes and megakaryocytes
this mutation leads to impaired T cell activation because the T cells are not able to form and maintain an immunological synapse and without a synapse, there’s impaired T cell activation
what are the characteristics of Wiskott-Aldrich Syndrome?
- recurrent bacterial infections
- thrombocytopenia
- small platelets***
- cytoskeletal defects
where is the WASP protein found?
WASP is expressed only in leukocytes and megakaryocytes
what causes DiGeorge’s Syndrome?
it’s a translocation in chromosome 22 that effects T-box 1 protein
it’s caused by single-copy (hemizygous) deletion of a small piece of chromosome 22 (22q11) containing the T-box 1 (TBX 1) gene
TBX 1 is a transcription factor with unknown function. Single copy depletion of TBX 1 results in incomplete development of thymic epithelia
what is DiGeorge’s Syndrom?
it’s a hemizygous deletion of 22q11 that leads to a single copy deletion of TBX1 gene
this causes failure of thymic epithelium development = poor T cell development since T cells develop in the thymus!
this leads to reduced T cell numbers and reduced humoral response
what are the characteristics of DiGeroge Syndrome?
- SCID phenotype (mild)
2. Incomplete development of thymus (and parathyroids) = low T cell numbers
what is MHCI deficiency?
it’s a mutation in the TAP transporter that takes proteins in the cytosol into the ER where they can bind to MHCI
if there’s a TAP mutation you have a problem because MHCI can’t generate a CD8 T cell response
this leads to chronic lung inflammation from recurrent viral infections in the lungs
what are MHCI deficient patients more susceptible to?
sustained respiratory infections with certain viruses, leading to chronic respiratory inflammation
what causes MHCII deficiency?
a mutation in CIITA trans-activator gene that turns on expression of MHCII
CIITA is a transcription factor that binds to the promoter region of the MHCII genes
what is MHCII deficiency?
it’s a mutation in CIITA trans-activator gene that turns on expression of MHCII
if there a mutation in CIITA gene then there’s no expression of MHCII gene which means there’s no CD4 T cell response
MHCII is required for positive selection and activation of CD4T cells so without MHCII there’s no active CD4 T cells
without CD4 T cells, you’ll get recurrent infections because CD4 T cells are required for activation of naive B cells so there’s no antibody response
what causes x-linked agammaglobulinemia?
mutation in Btk gene
Btk plays a key role in intracellular signaling from the B cell receptor, and is, thus, required for the differentiation of pre-B cells to B cells
so a mutatied Btk gene results in blockade of B cell development at the pre-B cell stage
what is x-linked agammaglobulinemia?
mutation in Btk gene which leads to no B cells = recurrent infections
Btk plays a key role in intracellular signaling from the B cell receptor, and is, thus, required for the differentiation of pre-B cells to B cells
so people with XLA dont have antibodies!!!
what are XLA patients more susceptible to?
extracellular bacterial pathogens
this is because XLA have no antibodies due to a block of B cell development – antibodies are needed to facilitate bacterial uptake by phagocytes via opsonization
how do you treat XLA?
gamma globulin administration
systemic antibiotics
this is because their B cells never develop due to Btk mutation so they can’t make anitbodies
what causes a CD40L deficiency?
a mutation in the CD40L gene
so then there’s no CD40L on T helper cells
upon initial exposure to an antigen, B cells produce IgM, which is much less efficient than IgG in neutralization and opsonization
antibody isotype switching from IgM to IgG, IgA, and IgE requires “help” from CD4 T cells
antigen-specific help is provided by molecular interaction between CD40 on B cells and CD40L on T cells
so CD40L gene mutation leads to defect in isotpe switching
what is CD40L deficiency?
CD40L gene mutation
you need CD40L to be signal 2 in T cell-B cell interaction
without CD40L there is no isotype switching and you only have IgD and IgM
this leads to x-linked hyper-IgM syndrome and recurrent infections
sidenote: CD40 deficiency would clinically present the same exact way
where is the CD40L gene located?
x chromomosome
where is the CD40 gene located?
chromsome 20
what is AID deficiency?
AID is involved in isotype switching and somatic hypermutation
so when there’s a mutation in the AID gene, there’s no somatic hypermutation or isotype switching which leads to recurrent infections
RAG-mediated VDJ recombination is responsible for the initial antibody repertoire of B cells in the BM
the secondary phase of diversification occurs in antigen-activated B cells via somatic hypermutation (leading to affinity maturation) and isotype switching – AID is required for both somatic hypermutation and isotype switching
patients with AID deficiency produce only IgM!!
what is the difference between AID deficiency and CD40L deficiency?
AID deficiency has germinal center formation just without isotype switching
CD40L deficiency doesn’t even have germinal center formation because there isn’t good early T cell help and no T cell-B cell interaction to pair up and head to the germinal center
what is X-linked hypohydrotic ectodermal dysplasia with ID?
mutation in NFκB essential modulator (NEMO) gene
ligation of of CD40 on B cells with CD40L on T cells triggers NFkB activation in B cells, leading to isotype switching
so if there’s a mutation in the NEMO gene there will be no isotype switching and you’ll have recurrent infections
what is the clinical presentation of X-linked hypohydrotic ectodermal dysplasia with ID?
mutation in NEMO gene leads to no NFκB expression which is involved in isotype switching
there is abnormal sweat gland, hair, and tooth development
so they won’t be able to sweat, they’ll have crooked teeth and their hair won’t be well developed
what causes X-linked lymphoproliferative syndrome?
XLP is a mutation in the SAP gene
SH2-domain containing gene 1A (SH2S1A) encodes a protein named SLAM-associated protein (SAP)
SAP interacts with cytoplasmic tails of SLAM on T cells and 2B4 (CD244) on NK cells, leading to the recruitment of Fyn, activation of the killing machinery, and inhibition of interferon γ production
so SAP mutation inhibits the ability of the SLAM receptor to induce killing of virus by NK and T cells
what is X-linked lymphoproliferative syndrome?
it’s a mutation in the SAP gene – SAP is important in viral infections for regulation cytokine production, especially for NK and T cells
so a SAP mutation would mean you won’t be able to functionally signal to NK and T cells
there will also be a killing defect and high levels of INF-γ
high INF-γ levels will skew your TH1 responde and lead to uncontrolled EBV infections –> EBV will lead to B cell lymphoma
so SAP mutation inhibits the ability of the SLAM receptor to induce killing of virus by NK and T cells
in normal cells if killing is high, INFγ is low
what is NK cell defect?
virally infected host cells are usually eliminated by NK cells and CD8 T cells
NK cells are looking for cells with low MHCI expression
herpes simplex virus (HSV) infection downregulates surface expression of MHC class I molecules, which are required for CD8 T cell activation
so HSV-infected host cells can be eliminated only by NK cells
so then, patients with NK cell defect exhibit increased susceptibility to HSV infection
what causes leukocyte adhesion deficiency?
mutation of CD18 gene leads to impaired leukocyte migration and impaired phagocytosis
what is LAD?
CD18 is β2 integrin
CD18 combines with CD11a, CD11b, and CD11c to form LFA-1, Mac-1/CR3, and CR4 receptors
these are responsible for complement and fibrinogen binding
LFA-1, Mac-1/CR3, and CR4 function as adhesion molecules mediating leukocyte adhesion to counter-receptors (ICAMs) and as complement receptors
without LFA1, Mac-1, and CR4 on your WBCs you’ll have issues with migration, and phagocytosis
this will cause tons of infections because WBC can’t get out of the blood to the tissues
what causes chronic granulomatous disease?
it’s a mutation in the NADPH oxidase gene
what is chronic granulomatous disease?
NADPH oxidase gene mutation
without NADPH oxidase there’s no oxygen radicals to kill pathogens that have been phagocytosed
eventually you get granulomas which are aggregates of phagocytic cells that can’t kill what’s inside them
so patients with chronic granulomatous disease have persistent infections with bacteria and fungi and develop granulomatous lesions
why does X-linked SCID result in few, if any, T cells?
lack of IL2R and IL7R results in no T cell proliferation
what immune defect does ADA deficiency cause?
no T or B cells
what immune defect does PNP deficiency cause?
no T or B cells
what immune deficiency does SCID cause?
no T cells
what immune deficiency does DiGeorge syndrome cause?
thmic aplasia that causes variable numbers of t and B cells
which abnormalities can cause SCID?
- ADA deficiency
- PNP deficiency
- γ chain deficiency
- autosomal DNA repair defect
what immune deficiency does MHCI deficiency e cause?
TAP mutation that leads to no CD8 T cells
susceptible to chronic lung and skin inflammation
what immune deficiency does MHCII deficiency cause?
lack of expression of MHCII leads to no CD4 T cells
what is the specific abnormality and immune defect associated with Wiskott-Aldrich syndrome?
abnormality: x-linked defective WASP gene
immune defect: leads to defective anti-polysaccharide antibody and impaired T-cell activation responses
increased suceptibility to encapsulated extracellular bacteria
what is the specific abnormality and immune defect associated with x-linked agammaglobulinemia?
abnormality: loss of Btk tyrosine kinase
immune defect: no B cells
susceptible to extracellular bacteria and viruses
what is the specific abnormality and immune defect associated with X-linked hyper-IgM Syndrome?
abnormality: defective CD40L
immune defect: no isotype switching
suceptible to extracellular bacteria
what is the specific abnormality and immune defect associated with common variable immunodeficiency?
abnormality: unknown
immune defect: defective IgA and IgG production
suceptible to extracellular bacteria
what is the specific abnormality and immune defect associated with selective IgA?
abnormality: unknown, MHC linked
immune defect: no IgA synthesis
suceptible to respiratory infections
what are NK cell defect patients suceptible to?
herpes virus
what is the specific abnormality and immune defect associated with -linked lymphoproliferative syndrome?
abnormality: SH2D1A mutation
immune defect: inability to control B cell growth
suceptible to EBV and B cell tumors
what is the specific abnormality and immune defect associated with ataxia telangiectasia?
abnormality: gene with PI 3-kinase homology
immune defect: T cells reduced
susceptible to respiratory infections
what is the specific abnormality and immune defect associated with Bloom’s syndrome?
abnormality: defective DNA helicase
immune defect: T cells reduced
reduced antibody levels
susceptible to respiratory infections
what is the specific abnormality and immune defect associated with LAD?
abnormality: defective CD18
immune defect: defective migration of phagocytes into infected tissues
what is the specific abnormality and immune defect associated with chronic granulomatous disease?
abnormality: defective NADPH oxidase so phagocytes can’t produce superoxide
immune defect: impaired killing of phagocytesed bacteria
what happens when there’s C1, C2, C4 deficiency?
immune-complex diseases
what happens when there’s C3 deficiency?
susceptibility to capsulated bacteria
what happens when there’s C5-C9 deficiency?
susceptibility to Neisseria
