Immuno: Primary Immune Deficiencies Pt.4

Question 1

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

1. SCID
2. Di George
3. BLS Type 2

Answer 1

1. SCID
   
   • CD4 low
   • CD8 low
   • B cells normal/low
   • IgM normal/low
   • IgG low
2. Di George
   
   • CD4 low
   • CD8 low
   • B cells normal
   • IgM normal
   • IgG normal/low
3. BLS Type 2
   
   • CD4 low
   • CD8 normal
   • B cells normal
   • IgM normal
   • IgG low

Question 2

Outline some management approaches for immunodeficiency involving T cells.

Answer 2

• 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)

Question 3

Describe the stereotypical presentation in the following lymphocyte deficiencies.

1. X-linked SCID
2. IFN-gamma receptor deficiency
3. 22q11.2 deletion syndrome
4. Bare lymphocyte syndrome type 2

Answer 3

1. 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
2. IFN-gamma receptor deficiency: young adult with chronic infection with Mycobacterium marinum
3. 22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
4. 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.

Question 4

What determines the class of immunoglobulin?

Answer 4

Heavy chain

Question 5

What determines the effector function of immunoglobulin?

Answer 5

Constant region of the heavy chain

Question 6

Briefly outline the functions of antibodies.

Answer 6

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

Question 7

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

Answer 7

• 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

Question 8

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

Answer 8

• 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

Question 9

Outline the pathophysiology of X-linked hyper IgM syndrome.

Answer 9

• 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

Question 10

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

Answer 10

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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

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

Question 13

Outline the clinical phenotype of common variable immunodeficiency.

Answer 13

• 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)

Question 14

What is the prevalence of selective IgA deficiency?

Answer 14

1 in 600

Question 15

What are the clinical features of antibody deficiency?

Answer 15

• Bacterial infections (e.g. Staphylococcus)
• Toxins (e.g tetanus)
• Some viral infections (e.g. enterovirus)

Question 16

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

Answer 16

• 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 prodution is a surrogate marker for CD4+ T helper cell function

Question 17

Which peak repesents immunoglobulin in protein electrophoresis?

Answer 17

Gamma peak

NOTE: albumin produces a large peak

Question 18

Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in:

1. SCID
2. Bruton’s X-linked Hypogammaglobulinaemia
3. X-linked Hyper IgM syndrome
4. Selective IgA deficiency
5. Combined variable immunodeficiency

Answer 18

1. SCID
   
   • CD4 low
   • CD8 low
   • B cell low
   • IgM low
   • IgG low
   • IgA low
2. Bruton’s X-linked Hypogammaglobulinaemia
   
   • CD4 normal
   • CD8 normal
   • B cell low
   • IgM low
   • IgG low
   • IgA low
3. X-linked Hyper IgM syndrome
   
   • CD4 normal
   • CD8 normal
   • B cell normal
   • IgM high
   • IgG low
   • IgA low
4. Selective IgA deficiency
   
   • CD4 normal
   • CD8 normal
   • B cell normal
   • IgM normal
   • IgG normal
   • IgA low
5. Combined variable immunodeficiency
   
   • CD4 normal
   • CD8 normal
   • B cell normal
   • IgM normal
   • IgG low
   • IgA low

Question 19

Outline the management approaches to immunodeficiency involving B cells.

Answer 19

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

Question 20

Describe a stereotypical presentation of the following diseases:

1. Common variable immunodeficiency
2. X-linked hyper IgM syndrome
3. Bruton’s X-linked hypogammaglobulinaemia
4. IgA deficiency

Answer 20

1. Common variable immunodeficiency: adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
2. X-linked hyper IgM syndrome: recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG
3. 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
4. IgA deficiency: recurrent respiratory tract infections, absent IgA, normal IgM and IgG