L19 - Aids and Immunodeficiency Flashcards
Immunodeficiencies: what are they and what can they cause?
Conditions where the body has a decreased ability to fight infections and other diseases
Immunodeficiencies can cause overactive immune responses:
* Autoinflammatory disorders
* Autoimmune disorders-defects in regulation or tolerance (covered in a previous lecture)
What are the stages of immunodeficiency?
Primary (inherited) Immunodeficiency
- defects in components of innate immunity
- defects in components of adaptive immunity
Secondary (acquired) Immunodeficiency
- HIV (AIDs)
- malnutrition, drug reactions
Primary immunodeficiency: what is it, how many genes result in it, what genes are they caused by, when are they normally diagnosed, and what are they grouped by?
Rare heterogeneous conditions that are immune-related and often lead to immunodeficiency
> 300 distinct genetic defects identified so far
Rare autosomal or x-linked recessive conditions
Normally diagnosed early in infants
Often grouped by the component of the immune system most affected.
Autoinflammatory disorders: what are the examples, what are they caused by, what symptoms do they have, and what are their treatments?
Cryopyrin-associated periodic syndrome (CAPS)
- autosomal dominant mutations in cryopyrin (NLRP3) - recurrent episodes of fever, a hive-like rash; joint pain and swelling; red eyes; headaches, and if untreated can cause deafness or amyloidosis.
- Familial Mediterranean fever - mutations in gene encoding the inflammasome regulator pyrin - result in recurrent fevers, inflammation of the abdomen, chest and joints and can cause amyloidosis
Treatments for both can include drugs to target interleukin-1
Autoimmune disorders: what
- Autoimmune syndrome (IPEX) - defects in the Foxp3 gene (Tregs)
- Autoimmune lymphoproliferative syndrome (ALPS) - defects in Fas or FasL genes - lymphoproliferation, lymphadenopathy and splenomegaly, higher risk of lymphoma
requires monitoring and may need immunosuppressive agents e.g. if autoimmunity develops
Immunodeficiencies: what do they most often result in, and what parts of the immune system are compromised in infections with pyogenic bacteria, fungal infections, and recurrent viral infections?
Main consequence of most PIDs is increased susceptibility to opportunistic infections
- Pyogenic bacteria - antibody, complement, phagocytes
- Fungal infections - Th17
- Recurrent viral infections- T cells (Tc/Th1)
Defects in the innate immune response: what conditions result in defects in phagocyte production, adhesion, activation, and killing?
- Phagocyte production - Congenital neutropenia (e.g. CXCR4)
- Phagocyte adhesion - Leucocyte adhesion deficiencies (LAD-1, LAD-2) - x2 neutrophil amount in circulation but less are found in inflammation than needed
- Phagocyte activation - Defects of PRR sensing and signalling
- Phagocyte killing: Chronic granulomatous disease (CGD) [Chediak-Higashi syndrome]
Defects of Adaptive Immunity: how can it happen and what form of combined immunodeficiency may occur
Th needed for B cell activation, Ab production, isotype switching - defects in function of the T cell compartment often affect B cells too as a result
The most severe forms of combined immunodeficiency involve complete failure of T cell development– severe combined immunodeficiencies (SCID)
SCID: what is it, what mutations cause it, and what occurs within it?
Severe combined immune deficiency
Mutation in several different genes can cause SCID
- Involves a block in T-cell development
- A direct or indirect B cell deficiency
- NK cells may also fail to develop
Leccy
Defective cytokine signalling in T cell precursors
- X-linked SCID (T-B+NK- SCID) - most frequent form of SCID, mutations in the common γ chain (c), a shared component of receptors for the IL-2 cytokine family - IL2, 4, 7, 9, 15 and 21
Affects males - Also was known as ‘the bubble boy disease’
- JAK-3 SCID (T-B+NK- SCID) - clinically and immunologically indistinguishable from X-linked SCID, not X-linked (Autosomal recessive)
IL7R SCID (T-B+NK+ SCID)
Affects only T and not NK cells
Defects resulting in B cell deficiency
Mutations that specifically target B cells
Most common form of immunodeficiencies
N.B. Normally free of infection up to 7-9 months due to maternal antibodies
Recurrent bacterial infections, particularly encapsulated pyogenic bacterial which require opsonisation and clearance
Two broad classes:
Absence of mature B cells
Presence of mature B cells (but with some impairment of response)
Treatment with IVIG
X-linked agammaglobulinemia (XLA)
Absence of mature B cells
Mutations occurs at the pre-B-cell stage resulting in arrested B cell development
Selective X-inactivation preserves the wt allele in female carriers
Profound deficiency of B cells and circulating antibodies
Recurrent pyogenic bacterial infections
Presence of mature B cell with impaired function i.e. impaired antibody
Most common PIDs
Levesl of B cells are normal
Only some affected genes have been characterised – in most cases the genetic cause is not yet defined
Defects in Ig often limited to one or more antibody isotype
Clinically and genetically heterogeneous
Often undiagnosed until late childhood/adulthood
Typically mild recurrent infections
Defects resulting in deficient T/B and T/APC communication: Hyper IgM syndromes
Mutation in CD40L gene
(expressed by activated T cells)
Unable to engage with CD40 on B cells and APC
Failure of B cells to undergo isotype switching
Impaired activation of macrophages and DC and production of IL12
- impaired type I immunity
Igs: what is the first one made in an immune response and what happens if the body’s isotype switching ability is impaired?
If you can’t isotype switch you will only make IgM (remember this is the first Ig we make in an immune response).
Again the key concept is because something on a T helper cells is impacted and they are central to SO many immune functions that the ipact is on B cell antibody function and macrophage/dendritic cells functions
