Immuno 4: Primary Immune Deficiencies 2 Flashcards
What is the most common form of SCID ?
What mutation + how does this lead to the diease?
X-linked SCID
Mutation in common gamma chain on Xq13.1:
- gamma chain = important component of Cytokine receptors
- Mutation leads -> inability to respond to cytokines -> causing arrest in T and NK cell development + arrest in production of immature B cells
Describe the typical cell counts you would expect to see in X-linked SCID.
Very low T cells
Very low NK cells
Normal or increased B cells
Low immunoglobulin
No IgA or IgG because CD4+ Th cells needed for Isotype switching.
Pathophys of ADA deficiency?
Typical cell counts?
Adenosine deaminase enzyme (ADA) is deficient which causes failure of lymphocyte maturation
Low T, NK and B cells
Why are infants with SCID protected in the first 3 months ?
maternal IgG is still present in the infants circulation and provides immunity
What is the function of CD4+ T cells in the immune response ?
What are they important in protecting against?
MoA of killing by these cells?
- activates B cells
- activates CD8+ cytotoxic T cells
Viral infections + Tumours
Injection of perforin + granzyme
Fas ligand
Which genetic syndrome causes the thymus to be underdeveloped and therefore a reduced number of T cells in children?
DiGeorge syndrome
T cell numbers recover with age
List the main pathologies of DiGeorge syndrome ?
Developmental defect where?
immunological consequences?
CATCH 22
Cardiac abnormalities ( Tetralogy of fallot)
Abnormal facies (low set ears, high forehead)
Thymic aplasia (Reduced T cells)
Cleft palate
Hypocalcaemia (hypoparathyroidism)
22nd chromosome mutation 22q11
(There is developmental defect in the pharyngeal pouch)
Immunological consequences?
- Normal B cell count
- Low T cell count
- Homeostatic proliferation with age (T cell numbers increase with age)
- Immune function is mildly impaired and tends to improve with age
What syndrome causes a profound deficiency in CD4+ T cells but normal numbers of CD8+ T cells ? How?
Bare Lymphocyte syndrome -Type 2 (BLS type 2)
Absent expression of MHC class II molecules. (Means that T cells cant undergo affinity selection in the thymus to become CD4+)
Why do you get a reduction/absence in IgG and IgA immunoglobulins with CD4+ T cell defficiency (e.g in BLS type2) ?
The CD4+ T helper cells are involved in B cell Isotope switching so you have IgM B cells but cant switch to IgG/ IgA in the germinal centres.
What is the definitive treatment of SCID and BLS type 2 ?
Haematopoeitic stem cell transplant
How do you treat ADA SCID ?
Enzyme replacement therapy
Which bacterial infection are patients with an IFN gamma deficiency particularly susceptible to ?
Recurrent Mycobacterium Marinum infections (atypical mycobacterium)
22q 11.2 deletion syndrome is also known as ???
DiGeorge syndrome
Defect in the development of the pharyngeal pouch
Is the IgM B cell response T cell dependent ?
No
How do CD4+ T cells help B cells undergo B cell differentiation (isotype switching)?
CD40 ligand is expressed on CD4+ Th cells and this acts on CD40 receptors on B cells causing isotope switching.
Which part of an Antibody identifies pathogens/toxins ?
Fab (fragment antigen-binding) region
Which part of an antibody interacts with Complement/phagocytes/NK cells ?
Fc (ragment crystallizable) region
Bruton’s X linked agammaglobulinaemia pathophysiology?
An abnormal B cell tyrosine kinase (BTK) gene
Prevents the maturation of B cells at that point at which they emerge from the bone marrow
This results in the absence of mature B cells and, hence, an absence of antibodies
Which X-linked syndrome is associated with failure of B cell maturation and isotype switching causing an elevated serum IgM but no IgG/IgA? How does it do this?
Hyper IgM syndrome
Mutation in CD40 ligand on T cells which means CD4+ T helper cells cant help B cells to undergo Maturation in germinal centres
Which immune deficiency disease is associated with poor response to immunisation, with low IgG/ IgA / IgM ?
What are they at risk of?
Common variable immune deficiency
Not much known but it is a defect in production of Immunoglobulins
They get a lot of inflammatory and auto-immune diseases
Which immunodeficiency disease is associated with recurrent respiratory tract infections, low IgA levels and normal levels of all other immunoglobulins ?
IgA deficiency
Which genetic mutation is associated with Wiskott-Aldrich syndrome ?
WASp gene
Which mutation is associated with Bare lymphocyte syndrome type 2 ?
MHC class II
Which mutation is associated with SCID ?
IL-2 receptor
Which mutation is associated with Bruton’s X-Linked Agammaglobulinaemia ?
BTK gene
Which lymphocytes respond to foreign HLA-DR types ?
CD4+ T cells
Which lymphocytes respond to foreign HLA-B types ?
CD8+ T cells
Patient presents with recurrent nose bleeds, easy bruising and blood in the stool.
Blood tests reveal a thrombocytopenia, elevated IgA and IgE and reduced IgM levels.
Most likely diagnosis ?
Wiskott-Aldrich syndrome
Patient presents with jaundice and hepatomegaly. His bloods show a low CD4+ T cell level but normal CD8+ level.
Most likely Diagnosis?
Bare lymphocyte syndrome Type 2
Young girl presents with recurrent skin infections with a normal neutrophil count and a NTB test remains colourless
Most likely diagnosis ?
Chronic granulomatous disease.
Caused by a deficiency in NADPH which causes absence of the respiratory burst.
Typical levels of CD4, CD8, B cells, IgM and IgG that you would expect to see in the following diseases:
SCID
Di George
BLS Type II
SCID: CD4 low CD8 low B cells normal/low IgM normal/low IgG low
Di George: CD4 low CD8 low B cells normal IgM normal IgG normal/low
BLS Type 2: CD4 low CD8 normal B cells normal IgM normal IgG low
Describe the stereotypical presentation in the following lymphocyte deficiencies:
X-linked SCID
IFN-gamma receptor deficiency
Di George Syndrome
BLS Type II
X-linked SCID: severe recurrent infections from 3 months of age, CD4 and CD8 are absent, B cells present, Ig low, normal facial features and echocardiogram
IFN-gamma receptor deficiency: young adult with chronic infection with Mycobaterium marinum
22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
Bare Lymphocyte Syndrome Type 2: 6-month old baby with two recent serious bacterial infections. T cell present but only CD8. IgM present but IgG is low
Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in:
SCID
- Bruton’s X-linked Hypogammaglobulinaemia
- X-linked Hyper IgM Syndrome
- Selective IgA deficiency
- Combined variable immunodeficiency
SCID: CD4 low CD8 low B cell low IgM low IgG low IgA low
Bruton’s X-linked Hypogammaglobulinaemia: CD4 normal CD8 normal B cell low IgM low IgG low IgA low
X-linked Hyper IgM Syndrome: CD4 normal CD8 normal B cell normal IgM high IgG low IgA low
Selective IgA deficiency: CD4 normal CD8 normal B cell normal IgM normal IgG normal IgA low
Combined variable immunodeficiency : CD4 normal CD8 normal B cell normal IgM normal IgG low IgA low
Describe a stereotypical presentation of the following diseases:
Common variable immunodeficiency
X-linked Hyper IgM syndrome
Bruton’s X-linked hypogammaglobulinaemia
IgA deficiency
Common variable immunodeficiency: adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
X-linked hyper IgM syndrome: recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG
Bruton’s X-linked hypogammaglobulinaemia: 1-year old boy. Recurrent bacterial infections, CD4 and CD8 cells present, B cells absent, absent IgG, IgA and IgM
IgA deficiency: recurrent respiratory tract infections, absent IgA, normal IgM and IgG
Which peak represents immunoglobulin in protein electrophoresis?
Gamma peak
NOTE: albumin produces a large peak
What are the clinical features of antibody deficiency?
Bacterial infections (e.g. Staphylococcus)
Toxins (e.g. tetanus)
Some viral infections (e.g. enterovirus)
Summary of T Lymphocyte problems + examples?
Failure of lymphocyte precursors (X-linked SCID)
Failure of thymic development (DiGeorge)
Failure of HLA molecule expression (BLS)
Failure of signalling , cytokine production and effector function (IFN-gamme / receptor deficiency, IL12 or receptor deficiency)
Summary of B Lymphocyte problems + examples?
Failure of lymphocyte precursors (SCID)
Failure of B cell maturation (Bruton’s X-linked agammaglobulinaemia)
Failure of T cell co-stimulation (X-linked Hyper IgM syndrome)
Failure of production of IgG antibodies (Common variable immune deficiency, Selective antibody deficiency)
Failure of IgA production (Selective IgA deficiency)
Name a defect in stem cells that causes SCID and name the gene that is mutated.
Reticular dysgenesis – adenylate kinase 2 (AK2) - this causes the most severe form of SCID
NOTE: this is a mitochondrial energy metabolism enzyme
