Primary Immune Deficiency 2 Flashcards by Ambreen Muhammed

Briefly outline how lymphocytes are derived from stem cells in the bone marrow.

Some will develop into pre-T cells which leave the bone marrow and undergo thymic selection in the thymus to become mature CD4 or CD8 T lymphocytes
Pre- and Pro-B cells can leave the bone marrow and become IgM B cells
These cells can then produce an early IgM response and become IgM memory and plasma B cells
They can also undergo a germinal centre reaction and undergo class switching and affinity maturation

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Name a defect in stem cells that causes SCID and name the gene that is mutated.

Reticular dysgenesis – adenylate kinase 2 (AK2)

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What is the most common type of SCID?

X-linked SCID

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Which mutation is responsible for X-linked SCID?

Mutation in common gamma chain on Xq13.1
This is a component of many cytokine receptors leading to an inability to respond to cytokines, causing arrest in T and NK cell development and the production of immature B cells

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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

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Describe the pathophysiology of adenosine deaminase deficiency.

This is an enzyme required by lymphocytes for cell metabolism
ADA deficiency leads to failure of maturation along any lineage

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Describe the typical cell counts you would expect to see in ADA deficiency.

Very low T cells
Very low B cells
Very low NK cells

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Describe the clinical phenotype of SCID.

Unwell by 3 months age (once protection by maternal IgG dissipates)
Infections of all types
Failure to thrive
Persistent diarrhoea
Unusual skin disease (colonisation of infant’s empty bone marrow by maternal lymphocytes can cause a graft-versus-host disease-like condition)
Family history of early death

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What are the two mechanisms by which CD8+ T cells kill cells?

Perforin and granzyme

Fas ligand

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Which cellular insults are CD8+ T cells particularly important in protecting against?

Viral infections

Tumour

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In which group of syndromes does the thymus gland fail to develop properly?

22q11.2 deletion syndromes (e.g. Di George syndrome)

This is characterised by failure of development of the pharyngeal pouch

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What are the main clinical features of 22q11.2 deletion syndromes?

Facial abnormalities (high forehead, low set ears, cleft palate, small mouth and jaw)
Underdeveloped parathyroid gland (resulting in hypocalcaemia)
Oesophageal atresia
Underdeveloped thymus
Complex congenital heart disease

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What are the immunological consequences of an underdeveloped thymus gland?

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

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What condition is caused by a deficiency of MHC Class II? Briefly outline its pathophysiology.

Bare lymphocyte syndrome (BLS) type 2

Deficiency of MHC Class II means that CD4+ T cells cannot be selected in the thymus leading to CD4+ T cell deficiency

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Which defect leads to Bare lymphocyte syndrome?

Defects in the regulatory proteins involved in expression of class II genes:
• Regulatory factor X
• Class II transactivator

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Describe the typical cell counts that you would expect to see in Bare Lymphocyte syndrome type 2.

Normal CD8+
Very low CD4+
Normal B cell count
Low IgG

Outline the clinical phenotype of bare lymphocyte syndrome.

Unwell by 3 months of age
Infections of all types
Failure to thrive
Family history of early death

What are the common clinical features of T lymphocyte deficiencies?

Viral infections (e.g. CMV)
Fungal infections (e.g. PCP)
Some bacterial infections (e.g. TB, salmonella)
Early malignancy

List some investigations that may be used for suspected T cell deficiencies.

Total white cell count and differentials
Lymphocyte subsets
Immunoglobulins
Functional tests of T cell activation and proliferation
HIV test

How are lymphocyte counts different in children compared to adults?

Higher in children compared to adults

Describe the typical levels of CD4, CD8, B cells, IgM and IgG that you would expect to see in the following diseases:
a. SCID

b. Di George
c. BLS Type 2

a.	SCID 
CD4 low 
CD8 low 
B cells normal/low 
IgM normal/low 
IgG low 
b.	Di George
CD4 low 
CD8 low 
B cells normal 
IgM normal 
IgG normal/low 
c.	BLS Type 2
CD4 low 
CD8 normal 
B cells normal 
IgM normal 
IgG low

Outline some management approaches for immunodeficiency involving T cells.

Aggressive prophylaxis/treatment of infection
Haematopoietic stem cell transplantation
Enzyme replacement therapy (e.g. PEG-ADA for ADA deficiency)
Gene therapy
Thymic transplantation (in Di George syndrome)

Describe the stereotypical presentation in the following lymphocyte deficiencies.
a. X-linked SCID:
b. IFN-gamma receptor deficiency:
c. 22q11.2 deletion syndrome:
d. Bare Lymphocyte Syndrome Type 2:

a. 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
b. IFN-gamma receptor deficiency: young adult with chronic infection with Mycobaterium marinum
c. 22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
d. 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

What determines the class and effector function of immunoglobulin?

heavy chain

Constant region of the heavy chain

27. Briefly outline the functions of antibodies.

Identification of pathogens and toxins (particularly against extracellular pathogens) Interacts with other components of the immune response (e.g. completement, phagocytes, NK cells) Important in defence against bacteria

28. Outline the pathophysiology of Bruton’s X-linked hypogammaglobulinaemia.

Prevents the maturation of B cells at that point at which they emerge from the bone marrow Caused by an abnormal B cell tyrosine kinase (BTK) gene This results in the absence of mature B cells and, hence, an absence of antibodies

29. Outline the clinical phenotype of Bruton’s X-linked hypogammaglobulinaemia.

Boys present in the first few years of life Recurrent bacterial infections (e.g. otitis media, pneumonia) Viral, fungal and parasitic infections Failure to thrive

30. Outline the pathophysiology of X-linked hyper IgM syndrome.

Blocks the maturation of IgM B cells through germinal centres into B cells that produce other classes of immunoglobulin (i.e. prevents germinal centre reactions) Caused by a mutation in the CD40 ligand gene This is technically a T cell problem, however, it means that CD4+ T helper cells cannot provide help to B cells so they cannot undergo germinal centre reactions NOTE: CD40 ligand is encoded on Xq26

31. Describe the typical biochemical results you would expect to see in X-linked hyper IgM syndrome.

``` Normal B cells Normal T cells No germinal centre reactions High IgM Absent IgG, IgA and IgE (failure of isotype switching) ```

32. Outline the clinical phenotype of X-linked hyper IgM syndrome.

Boys present in the first few years of life Recurrent infections (mainly bacterial) Subtle abnormality in T cell function (predisposes to PCP, autoimmunity and malignancy) Failure to thrive

33. What is common variable immunodeficiency and what are the main features?

A group of disorders caused by some form of failure of differentiation of B lymphocytes Defined by: • Marked reduction in IgG, IgA and IgE • Poor/absent response to immunisation • Absence of other defined immunodeficiency

34. Outline the clinical phenotype of common variable immunodeficiency.

May present in adults or children Recurrent bacterial infection (often severe) Pulmonary disease (e.g. interstitial lung disease) GI disease (e.g. IBD-like disease) Autoimmune disease (e.g. AIHA) Malignancy (e.g. NHL)

37. List some investigations that may be used for suspected B cell deficiencies.

Total white cell count and differential Lymphocyte subsets Serum immunoglobulins and protein electrophoresis Functional tests of B cell function (e.g. measure IgG antibody against a specific pathogen (e.g. S. pneumoniae), if this is low, vaccinate using a killed vaccine and check levels again in 6-8 weeks) NOTE: IgG production is a surrogate marker for CD4+ T helper cell function

38. Which peak represents immunoglobulin in protein electrophoresis?

Gamma peak | NOTE: albumin produces a large peak

39. Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in: a. SCID b. Bruton’s X-linked Hypogammaglobulinaemia c. X-linked Hyper IgM Syndrome d. Selective IgA deficiency e. Combined variable immunodeficiency

``` a. SCID CD4 low CD8 low B cell low IgM low IgG low IgA low b. Bruton’s X-linked Hypogammaglobulinaemia CD4 normal CD8 normal B cell low IgM low IgG low IgA low c. X-linked Hyper IgM Syndrome CD4 normal CD8 normal B cell normal IgM high IgG low IgA low d. Selective IgA deficiency CD4 normal CD8 normal B cell normal IgM normal IgG normal IgA low e. Combined variable immunodeficiency CD4 normal CD8 normal B cell normal IgM normal IgG low IgA low ```

40. Outline the management approaches to immunodeficiency involving B cells.

Aggressive prophylaxis/treatment of infection Immunoglobulin replacement Immunisation (only if the patient is able to produce antibodies)

41. Describe a stereotypical presentation of the following diseases:

a. Common variable immunodeficiency: adult with bronchiectasis, recurrent sinusitis and development of atypical SLE b. X-linked hyper IgM syndrome: recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG c. 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 d. IgA deficiency: recurrent respiratory tract infections, absent IgA, normal IgM and IgG