Lecture 7- immunodeficiency Flashcards
what are Primary Immunodeficiency (PID) /Inborn Errors of Immunity (IEI)?
Now referred to as ‘inborn errors of immunity’
Are congenital - i.e. present from birth
Can be inherited or a result of a novel mutation
Can lead to minor increased risk of infections or an inability to control any infection
Inborn errors of immunity can be recessive or dominant
what was acquired immunodeficiency?
Also known as secondary immunodeficiency
Not present at birth, can occur at any time after birth
Can be due to:
Malnutrition
Infection
Age
Use of certain drugs, e.g. immuosuppressive drugs given to treat another disease
what are X-linked Severe Combined Immunodeficiency (SCID)?
Defect in IL2RG gene
This encodes a receptor that many cytokines use - common gamma chain
Some of these cytokines (e.g. IL-7) are required for T and B cell development
Most commonly affects males (as X-linked)
David Vetter received a bone marrow transplant from his sister - but this also led to infection with EBV
what is Retrovirus gene therapy as a treatment for ADA-SCID?
ADA: Adenoside deaminase deficiency
Mutation in this enzyme leads to a build up of intracellular S-adenosylhomocysteine which is toxic to lymphocytes
Previously, treatment was bone marrow transplant
Strimvelis was produced by GSK, licensed in 2017 and now used in the UK
A corrected version of ADA is inserted into the patient’s own bone marrow cells that are then returned to the patient
what is Chronic Granulomatous Disease?
Superoxide burst used by phagocytes to kill pathogens they have phagocytosed
Patients’ cells have no superoxide burst due to defects in NADPH enzymes
Multiple granulomas form as a result of defective elimination of bacteria
what is HIV infection?
HIV can lead to Acquired Immunodeficiency Syndrome
Almost 1 million people die from HIV/AIDS annual
South Africa, Namibia and Zimbabwe have the highest share of deaths across the world and often these deaths are linked to Tuberculosis infection
Treatment with Antiretroviral therapy can limit/prevent development of AIDS
what is IEI diagnosis?
In the US, 1 in 1200 people diagnosed
Often present as recurrent infection in children
Over 300 described
Can be due to mutation in one (monogenic) or a number of genes (polygenic)
Many PID remain poorly characterised with no known causal gene(s)
If Live Attenuated Vaccines can cause disease in some people, should we stop using them?
Most comments were about the benefit to the many from vaccines.
And serval comments about the importance if herd immunity which helps protects those who can’t have LAIVs.
Some commented that it might be helpful to identify people with IEI and then these people can receive help.
Some comments about health care being available to all and that we should find other solutions to LAIVs. And have improved screening got IEI.
what are Malnutrition driven immunodeficiency: complex network of effects and consequences?
Estimated that malnutrition is the underlying cause of 45% of global deaths in children below 5
Most deaths occurs in low income countries
Can affect cells of the innate and adaptive immunity
Malnourished individuals make poor responses to vaccines
how can Age-associated immunodeficiency affect many layers of the immune system
Often protected against infections they have met previously
BUT
Poor immune responses to new infections, vaccines and tumours
how are Autoimmune associated immunodeficiency and associated with severe outcomes in COVID-19?
Growing understanding that some people have antibodies to immune molecules including cytokines e.g. type 1 and 2 interferons, IL-17, and GM-CSF
Type I IFN signalling in infected cells limits viral replication or infection of neighbouring cells
Spotlight thrown on individuals with autoantibodies to type I Interferon (IFN) during the COVID19 pandemic
The auto-Ab prevent type I IFN from acting and leading to viral control
Anti-type 1 IFN antibodies found in about 10% of patients with life-threating COVID, with an increased predominance in males
Can treat with drugs that deplete B cells or plasma cells
how can the Delivery of live attenuated vaccines can reveal IEI?
Live Attenuated Vaccines (LAV): e.g. measles and polio, rotavirus
In people with PID, vaccination with LAVs can lead to severe disease
e.g. MMR vaccination of people with deficiencies in molecules involved in the type 1 IFN response can lead to encephalitis or hearing loss
Chicken pox (Varicella): disseminated virus strain found in some vaccinated individuals with T cell deficiencies
how can a Hyper-IgM syndrome - a defect in a T cell molecule leads to a poor Antibody response?
Often due to a mutation in the CD40L gene
Have B and T cells and IgM
But do not have class switched antibodies
B and T cells must interact to form a Germinal Centre response
Without a GC response, no high affinity class switched antibody can be produced
