Immunodeficiency I Flashcards
What is meant by immunodeficiency?
A congenital or acquired state where the immune response has:
- Missing components- genes missing or mutated so no protein is made.
- Non-functioning components- mutated gene makes protein but it doesn’t function.
- Incorrectly functioning components- mutated gene makes component but it either works partially or works too well! For example; mutation changes binding affinity with target protein in signalling pathway leading to either too great/prolonged a signal or too small/short a signal.
This leads to a deficiency in the function of the immune response and therefore increases susceptibility to infection. The immunodeficiency is the increased susceptibility to infection!
What are Opportunistic Infections?
Opportunistic infections are infections that do not occur in an immunocompetent individual and they are indicative of a deficiency in T cells.
These infections are ALL normally controlled by robust T cell-mediated immune responses. Such infections are indicative of severe combined immunodeficiencies or SCID.
Deficiencies in antibodies and B cells lead to BLANK
Deficiencies in antibodies and B cells lead to recurrent bacterial infections of the respiratory and gastrointestinal tract.
Deficiencies in neutrophils lead to BLANK
Deficiencies in neutrophils lead to recurrent and unresolving bacterial and fungal infections with granuloma/ulcers and very poor wound healing.
Deficiencies in complement lead to BLANK
Deficiencies in complement lead to Neisserial infections if the deficiency is in terminal components, immune complex mediated disease if it is in the classical pathway, and recurrent bacterial infections if it is C3.
Inheritance in Primary Immunodeficiency (PID):
Autosomal dominant- 1 normal functioning allele and 1 defective allele. The defective allele dominates the function of the normal product e.g. ALPS, hyper IgE, C1 inhibitor
Autosomal recessive- defective allele from both parents, both parents are carriers e.g. SCID caused by RAG1/2 deficiency
X linked- Recessive defect on the X chromosome. Males inherit defective gene from their mothers who are carriers e.g. X-linked agammaglobulinaemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-linked lymphoproliferative syndrome (XLP), X linked hyper IgM, Nuclear factor-kappa B essential modulator deficiency syndrome (NEMO), Properdin- X linked disease is a common mode of inheritance in primary immunodeficiency
These diseases are all very rare are the prevalence of these gene mutations in the human population is very low therefore autosomal recessive conditions are the rarest
Leukocyte adhesion deficiency (LAD):
- Inheritance is autosomal recessive
- LAD type 1- CD18 deficiency resulting in no tethering to endothelium (200 cases worldwide)
- LAD type 2-deficiency of fucose transport leading to Sialyl Lewis^x (CD15 deficiency)- no rolling of neutrophils (30 cases worldwide)
- LAD Type 3 Kindlin 3 deficiency- signaling problem leading to failure to migrate through endothelium (5 cases worldwide) (Rac 2 deficiency - L selectin expression autosomal dominant)
Consequences of LAD:
- Inability to recruit neutrophils to site of infection
- Delayed umbilical cord detachment
- Omphalitis- inflammation of umbilical cord
- Overwhelming bacterial infections with no pus- no neutrophils means no pus
- Poor wound healing
- Death without bone marrow/stem cell transplant
- These are very rare diseases as the prevelance of the mutated genes is very rare
LAD Type 1:
In LAD type 1, CD18 is missing which is part of LFA-1 therefore neutrophils cannot tightly bind to endothelium when ICAM 1 is upregulated during infection therefore neutrophils are not recruited to site of infection to remove bacterial pathogen.
LAD Type 2:
In LAD type 2 neutrophils can’t initiate rolling through binding to E-selectin on the endothelial surface via Sialyl Lewisx (s-Lex). Therefore they can’t to slow down and fail to be recruited to site of infection therefore infection is not neutralized.
LAD Type 3:
In LAD type 3, a mutation in the signaling protein kindlin 3 means neutrophils cannot change their shape to move between the endothelial cells therefore neutrophils are not recruited to site of infection and the bacterial pathogen is not destroyed.
Chronic granulomatous disease (CGD):
- Mutation in one of the proteins that make up NADPH oxidase of the neutrophil respiratory burst
- Inheritance X linked or autosomal recessive
- Most common gp91phox (X linked) therefore 70% of cases are boys
- Mothers are carriers and may be symptomatic due to inactivation of the normal X chromosome
- Autosomal recessive p21, p47, p67, p40
In CGD the NADPH oxidase is missing a
component therefore there is no respiratory
burst and no super oxide produced and the
bacteria or fungi is not killed
If you fail to kill the phagocytosed pathogen a granuloma is formed of immune cells which are attempting to isolate that pathogen from the rest of the organism. In chronic granulomatous disease (CGD) you get chronic production of small granuloma in sites of infection because the phagocytosed pathogen is not killed.
Consequences of CGD:
- Recurrent infections with catalase positive bacteria leading to pneumonia, abscesses of skin and infection of lymph nodes.
- Lung disease with Aspergillus
- Inflammatory bowel disease-like condition
- Granulomas- failure to clear phagocytosed bacteria
- Stem cell transplant (bone marrow) advised; gene therapy has been tried with limited success
Toll Like Receptor deficiencies:
Deficiencies in different TLR receptors or associated adaptor or signaling molecules lead to particular pathogen susceptibilities
We are going to look at two different TLR mediated immune deficiences.
- Herpes simplex encephalitis (HSE) -deficiency in TLR3 (Autosomal Dominant (AD)), TRIF (AD), UNC93B (Autosomal Recessive (AR)), uniquely susceptible to
Herpes simplex encephalitis on primary infection - IRAK4 (AR)/MyD88 (AR)- susceptibility to pyogenic (fever causing) bacteria that improves with age
Herpes simplex type 1 & HSE:
ds DNA virus typically associated with infection of oral mucosa or conjunctiva, causes “cold sores”. ds RNA is generated during its replication and is the natural target for TLR3
After initial infection virus is transported via sensory neurons to trigeminal nerves and ganglia where it establishes a latent infection.
Rarely it causes HSE. However, defects along the TLR3 signaling pathway are associated with increased susceptibility to HSE which can be recurrent.
Interestingly there is no susceptibility to other viruses. TLR3 would appear to be unique in central nervous system to protect from HSV-1 infections.
TLR3 has a unique signaling pathway that is not shared by other TLR. Mutations in TLR3, TRIF, TBK1, IRF3 or UNC93B can all result in HSE. If this pathway fails to operate Type 1 interferons are not produced. Type 1 interferons help to control viral infection by binding to IFN1 receptors on neighbouring cells leading to viral control.
Type 1 interferons bind to the Interferon alpha receptor which is composed of two different chains. The receptor triggers activation of Janus kinases JAK 1 and TYK2 and formation of the transcription factor ISGF3 (a heterodimer of STAT1/ STAT2 and IRF9), which drives the expression of type 1 interferon dependent genes that encode proteins that mediate the anti-viral response.
Consequences of TLR3 deficiency/HSE:
- High fever and right sided seizures due to uncontrolled HSV-1
- Recurrent herpes simplex encephalitis
- Can be fatal or lead to disability due to paralysis due to damage by uncontrolled viral infection in central nervous system
- No other viral susceptibilities
- HSV infection can be successfully treated with acyclovir if detected early enough
IRAK4/MyD88 deficiency:
Interleukin 1 receptor associated kinase 4 deficiency (IRAK4)
IL-1 receptors and TLR (except TLR3) share a common signal transduction pathway leading to NFkB activation
TLR are ligated by PAMPs on the surface of dendritic cells and macrophages leading to cellular activation and production of cytokines
Functioning IRAK4 or MyD88 is critical to the ability to make immune responses against TLR ligands and in response to IL-1via IL-1 receptors
Major source of proinflammatory cytokines
IL-1 b/IL-6 and TNFa are the main proinflammatory cytokines produced on initiation of the IRAK-4/MyD88 signaling cascades.
They lead to wide scale physiological responses as defined below. This includes the generation of a fever.
IL-6 also initiates the production of acute phase proteins from the liver which further help fight bacterial infections.
Consequences of IRAK4/MyD88 immunodeficiency:
- Severe recurrent invasive infection with pyogenic bacteria (pneumococcus/haemophilus)- 40% die by 8 year old from recurrent serious infection.
- Unusually weak febrile response- no fever they are much sicker than they look or feel therefore infection is only identified late in its course when it had become invasive.
- There susceptibility to recurrent invasive infections resolves with age to that of normal population by the age of 14years old. Likely antibody response protects by this age.
- They have a lifelong susceptibility to bacterial infections but they are not invasive.
- Early days of knowledge about this disease as only 49 patients identified IRAK4, 22 for MyD88.
Serum complement deficiencies:
- The complement system is a cascade system of serum proteins that is an effector mechanism for both innate and adaptive immunity both tagging pathogens for destruction and directly killing certain bacterial species through direct lysis.
- It is split into 3 pathways: Classical, Alternative and Mannan binding lectin pathways. They have common terminal components and common outcomes but different pathogen initiators
- There are also many control proteins which prevent uncontrolled lysis of the bodies own cells
- Deficiencies have been described for all complement proteins with a number of common outcomes depending on which pathway is affected.
- Deficiency in classical pathway early components leads to immune complex disease like Lupus but not increased susceptibility to infections.
- Deficiency in MBL leads to recurrent infections of the ears and upper respiratory tract which tends to resolve before adolescence
- Early components of alternative pathway lead to recurrent bacterial infections particularly with microorganisms with carbohydrate capsules (Pneumococcus/haemophilus) and Neisserial organisms.
- C3 common component to all 3 pathways leads to all of the above but infection is the most common feature.
Deficiency of the common terminal components ONLY leads to Neisserial infections and no other organisms.
