Immuno 4: Primary Immune Deficiencies 2

Question 1

What is the most common form of SCID ?

Answer 1

X-linked SCID

Question 2

Which cells are affected in X-linked SCID and why ?

Answer 2

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.

Question 3

Which cells are affected in ADA deficiency SCID and why ?

Answer 3

Low/ absent T, NK and B cells

Adenosine deaminase enzyme is deficient which causes failure of lymphocyte maturation

Question 4

Why are infants with SCID protected in the first 3 months ?

Answer 4

maternal IgG is still present in the infants circulation and provides immunity

Question 5

What is the function of CD4+ T cells in the immune response ?

Answer 5

• activates B cells

- activates CD8+ cytotoxic T cells

Question 6

Which genetic syndrome causes the thymus to be underdeveloped and therefore a reduced number of T cells in children?

Answer 6

DiGeorge syndrome

T cell numbers recover with age

Question 7

List 4 pathologies of DiGeorge syndrome ?

Answer 7

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)

Question 8

What causes a profound deficiency in CD4+ T cells but normal numbers of CD8+ T cells ?

What is the name of this syndrome ?

Answer 8

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)

Question 9

Why do you get a reduction/absence in IgG and IgA immunoglobulins with CD4+ T cell defficiency (e.g in BLS type2) ?

Answer 9

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.

Question 10

What is the definitive treatment of SCID and BLS type 2 ?

Answer 10

Haematopoeitic stem cell transplant

Question 11

How do you treat ADA SCID ?

Answer 11

Enzyme replacement therapy

Question 12

Which bacterial infection are patients with an IFN gamma deficiency particularly susceptible to ?

Answer 12

Recurrent Mycobacterium Marinum infections (atypical mycobacterium)

Question 13

22q 11.2 deletion syndrome is also known as ???

Answer 13

DiGeorge syndrome

Defect in the development of the pharyngeal pouch

Question 14

Is the IgM B cell response T cell dependent ?

Answer 14

No

Question 15

How do CD4+ T cells help B cells undergo B cell differentiation ?

Answer 15

CD40 ligand is expressed on CD4+ Th cells and this acts on CD40 receptors on B cells causing isotope switching.

Question 16

Which part of an Antibody identifies pathogens/toxins ?

Answer 16

Fab region

Question 17

Which part of an antibody interacts with Complement/phagocytes/NK cells ?

Answer 17

Fc region

Question 18

Which X-linked disease stops B cells leaving the bone marrow and hence is associated with a deficiency in mature B cells and antibodies ?

Answer 18

Bruton’s X linked agammaglobulinaemia

Question 19

Which X-linked syndrome is associated with failure of B cell maturation and isotype switching causing an elevated serum IgM but no IgG/IgA?

Answer 19

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

Question 20

Which immune deficiency disease is associated with poor response to immunisation, with low IgG/ IgA / IgM ?

Answer 20

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

Question 21

Which immunodeficiency disease is associated with recurrent respiratory tract infections, low IgA levels and normal levels of all other immunoglobulins ?

Answer 21

IgA deficiency

Question 22

Which genetic mutation is associated with Wiskott-Aldrich syndrome ?

Answer 22

WASp gene

Question 23

Which mutation is associated with Bare lymphocyte syndrome type 2 ?

Answer 23

MHC class II

Question 24

Which mutation is associated with SCID ?

Answer 24

IL-2 receptor

Question 25

Which mutation is associated with Bruton's X-Linked Agammaglobulinaemia ?

Answer 25

BTK gene

Question 26

Which lymphocytes respond to foreign HLA-DR types ?

Answer 26

CD4 + T cells

Question 27

Which lymphocytes respond to foreign HLA-B types ?

Answer 27

CD8+ T cells

Question 28

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 ?

Answer 28

Wiskott-Aldrich syndrome

Question 29

Patient presents with jaundice and hepatomegaly. His bloods show a low CD4+ T cell level but normal CD8+ level. Most likely Diagnosis?

Answer 29

Bare lymphocyte syndrome Type 2

Question 30

Young girl presents with recurrent skin infections with a normal neutrophil count and a NTB test remains colourless Most likely diagnosis ?

Answer 30

Chronic granulomatous disease. Caused by a deficiency in NADPH which causes absence of the respiratory burst.

Question 31

when is the thymus most active

Answer 31

fetal and neonatal period

Question 32

what is the most severe form of SCID and what is the mutation

Answer 32

reticular dysgenesis | mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

Question 33

phenotype of X linked SCID

Answer 33

very low/ absent T cell numbers normal/ increased B cell numbers very low/ absent NK cell numbers

Question 34

what is the clinical phenotype of SCID

Answer 34

``` unwell by 3 months infections of all types failure to thrive persistent diarrhoea unusual skin disease family history of early death ```

Question 35

what is the function of CD8+ T cells

Answer 35

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

Question 36

what is the function of CD4+ T helper cells

Answer 36

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)

Question 37

features of di George syndrome

Answer 37

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

Question 38

features of bare lymphocyte syndrome (BLS) type 2

Answer 38

``` 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

Question 39

clinical features of BLS type 2

Answer 39

unwell by 3 months infections of all types failure to thrive family history of early infant death

Question 40

how can we investigate T cell deficiencies

Answer 40

``` total WCC and differential (higher in children) lymphocyte subsets - CD4, 8, B, NK immunoglobulins functional tests HIV test ```

Question 41

how can we manage immunodeficiencies to do with T cells

Answer 41

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

Question 42

what is the classic presentation of X linked SCID

Answer 42

``` severe recurrent infections from 3 months CD4 and CD8 cells absent B cells present Ig low normal face and ECG ```

Question 43

what is the classical presentation of IFN g receptor deficiency

Answer 43

young adult with chronic infection with mycobacterium marinum

Question 44

what is the classical presentation of 22q 11.2 deletion syndrome

Answer 44

recurrent infections in childhood, abnormal facial features, CHD, normal B cells, low T cells, low IgA, low IgG

Question 45

what is the classical presentation of BLS type II

Answer 45

6 month baby with 2 recent serious bacterial infections T cells present but only CD8+ B cells present IgM present, IgG low

Question 46

what is brutons X linked hypogammaglobulinaemia

Answer 46

B cells do not mature no antibodies produced caused by an abnormal B cell TK gene (BTK) absence of mature B cells

Question 47

what are the clinical features of brutons X linked hypogammaglobulinaemia

Answer 47

boys present in first few years recurrent bacterial infections viral, fungal, parasitic failure to thrive

Question 48

features of hyper IgM syndrome

Answer 48

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 ```

Question 49

clinical phenoype of hyper IgM

Answer 49

boys present in first few years reuccent bacterial infections Pneumocystsis jirovecii failure to thrive

Question 50

features of common variable immunodeficiency

Answer 50

``` reduction in IgG, low IgA or IgM poor/absent response to immunisation recurrent bacterial infections pulmonary disease GI disease AI disease malignancy - NHL ```

Question 51

features of selective IgA deficiency

Answer 51

common many asymptomatic 1/3 have recurrent RTIs

Question 52

how can we investigate B cell deficiencies

Answer 52

``` 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 ```

Question 53

how can we manage immunodeficiency cause by B cells

Answer 53

aggressive prophylaxis/ treatment Ig replacement immunisation not worthwhile unless for selective IgA deficiency

Question 54

what is the classical presentation of common variable immunodeficiency

Answer 54

bronchiectasis, recurrent sinusitis, development of atypical SLE

Question 55

what is the classical presentation of X linked hyper IgM syndrome due to CD40L mutation

Answer 55

bacterial infections as a child, episode of PCP, high IgM, absent IgA, absent IgG

Question 56

what is the classical presentation of IgA deficiency

Answer 56

recurrent RTI absent IgA normal IgM normal IgG