Immuno 4: Primary Immune Deficiencies 2 Flashcards
What is the most common form of SCID ?
X-linked SCID
Which cells are affected in X-linked SCID and why ?
Reduction in T and NK cells
Increase in premature B cells
Because Common gamma chain is mutated which is an important component of Cytokine receptors. Therefore cant respond to cytokines causing early cell arrest in T and NK cells and production of immature B cells. No IgA or IgG because CD4+ Th cells needed for Isotype switching.
Which cells are affected in ADA deficiency SCID and why ?
Low/ absent T, NK and B cells
Adenosine deaminase enzyme is deficient which causes failure of lymphocyte maturation
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 ?
- activates B cells
- activates CD8+ cytotoxic T cells
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 4 pathologies of DiGeorge syndrome ?
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)
What causes a profound deficiency in CD4+ T cells but normal numbers of CD8+ T cells ?
What is the name of this syndrome ?
Absent expression of MHC class II molecules. (Means that T cells cant undergo affinity selection in the thymus to become CD4+)
Bare Lymphocyte syndrome -Type 2 (BLS type 2)
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 ?
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 region
Which part of an antibody interacts with Complement/phagocytes/NK cells ?
Fc region
Which X-linked disease stops B cells leaving the bone marrow and hence is associated with a deficiency in mature B cells and antibodies ?
Bruton’s X linked agammaglobulinaemia
Which X-linked syndrome is associated with failure of B cell maturation and isotype switching causing an elevated serum IgM but no IgG/IgA?
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 ?
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.
when is the thymus most active
fetal and neonatal period
what is the most severe form of SCID and what is the mutation
reticular dysgenesis
mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
phenotype of X linked SCID
very low/ absent T cell numbers
normal/ increased B cell numbers
very low/ absent NK cell numbers
what is the clinical phenotype of SCID
unwell by 3 months infections of all types failure to thrive persistent diarrhoea unusual skin disease family history of early death
what is the function of CD8+ T cells
cytotoxic cells
recognise peptides derived from IC proteins in association with HLA class I
HLA - A, B, C
kills cells directly - perforin, granzymes, expression of Fas ligand (causes)
important in the defence against viral infections and tumours
what is the function of CD4+ T helper cells
recognise peptides derived from EC proteins
presented on HLA class II
HLA - DR, DP, DQ
immunoregulatory functions via cell: cell interactions and expression of cytokines (provide help for a full B cell response, and some CD8+ T cell responses)
features of di George syndrome
22q11.2 deletion
thymus not fully developed
developmental defect of the pharyngeal pouch
high forehead, low ears, cleft palate, small mouth and jaw
underdeveloped parathyroid, oesophageal atresia, underdeveloped thymus, complex congenital heart disease
normal B cell numbers, low T cell numbers, immune function mildly improves with age
features of bare lymphocyte syndrome (BLS) type 2
defect in regulatory protein involved in expression of class II genes - regulatory factor X - class II transactivator leads to absent MHC class II deficiency of CD4+ cells
normal CD8+
normal B cell
low IgG or IgA
clinical features of BLS type 2
unwell by 3 months
infections of all types
failure to thrive
family history of early infant death
how can we investigate T cell deficiencies
total WCC and differential (higher in children) lymphocyte subsets - CD4, 8, B, NK immunoglobulins functional tests HIV test
how can we manage immunodeficiencies to do with T cells
aggressive prophylaxis/ treatment of infection
haematopoietic stem cell transplantation
enzyme replacement therapy - PEG-ADA, ADA SCID
gene therapy
thymic transplantation - to promote T development in di george syndrome
what is the classic presentation of X linked SCID
severe recurrent infections from 3 months CD4 and CD8 cells absent B cells present Ig low normal face and ECG
what is the classical presentation of IFN g receptor deficiency
young adult with chronic infection with mycobacterium marinum
what is the classical presentation of 22q 11.2 deletion syndrome
recurrent infections in childhood, abnormal facial features, CHD, normal B cells, low T cells, low IgA, low IgG
what is the classical presentation of BLS type II
6 month baby with 2 recent serious bacterial infections
T cells present but only CD8+
B cells present
IgM present, IgG low
what is brutons X linked hypogammaglobulinaemia
B cells do not mature
no antibodies produced
caused by an abnormal B cell TK gene (BTK)
absence of mature B cells
what are the clinical features of brutons X linked hypogammaglobulinaemia
boys present in first few years
recurrent bacterial infections
viral, fungal, parasitic
failure to thrive
features of hyper IgM syndrome
mutation in CD40 ligand gene (CD40L, CD154)
CD4+ cells cannot signal to B cells
blocks the maturation of IgM B cells through germinal centres
normal number of circulating B cells normal number of T cells no germinal centre development within LN and spleen failure of isotope switching elevated serum IgM undetectable serium IgG, A, E
clinical phenoype of hyper IgM
boys present in first few years
reuccent bacterial infections
Pneumocystsis jirovecii
failure to thrive
features of common variable immunodeficiency
reduction in IgG, low IgA or IgM poor/absent response to immunisation recurrent bacterial infections pulmonary disease GI disease AI disease malignancy - NHL
features of selective IgA deficiency
common
many asymptomatic
1/3 have recurrent RTIs
how can we investigate B cell deficiencies
total WCC lymphocyte subsets serum Ig and protein electrophoresis functional tests of B cell function protein electrophoresis - gamma peak = all the antibodies antibody deficient = no gamma peak
how can we manage immunodeficiency cause by B cells
aggressive prophylaxis/ treatment
Ig replacement
immunisation not worthwhile unless for selective IgA deficiency
what is the classical presentation of common variable immunodeficiency
bronchiectasis, recurrent sinusitis, development of atypical SLE
what is the classical presentation of X linked hyper IgM syndrome due to CD40L mutation
bacterial infections as a child, episode of PCP, high IgM, absent IgA, absent IgG
what is the classical presentation of IgA deficiency
recurrent RTI
absent IgA
normal IgM
normal IgG
