Immuno: Primary Immune Deficiencies 2 Flashcards
Name a defect in stem cells that causes SCID and name the gene that is mutated.
Reticular dysgenesis - adenylate kinase 2 (AK2)
NOTE: this is a mitochondrial energy metabolism enzyme
What is the most common type of SCID?
X-linked SCID
45% of all SCID
Which mutation is responsible for X-linked SCID?
- Mutation in common gamma chain on Xq13.1 –> impairs IL2 function
- 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
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
Describe the pathophysiology of ADA deficiency.
- ADA - adenosine deaminase
- This is an enzyme required by lymphocytes for cell metabolism
- ADA deficiency leads to toxin buildup –> failure of maturation along any lineage
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
Types of SCID
X-linked SCID
ADA deficiency
Reticular dysgenesis
Describe the clinical phenotype of SCID.
- Unwell by 3 months age (once protection by maternal IgG dissapates)
- Infections of all types
- Failure to thrive
- Persistant 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
What are the two mechanisms by which CD8+ T cells kill cells?
Perforin and granzyme (cytoxic granule release)
Fas ligand
Which cellular insults are CD8+ T cells particularly important in protecting against?
- Viral infections
- Tumour
Outline the immunoregulatory functions of CD4+ T cells.
- Provide help to mount a full B cell response
- Provide help for some CD8+ T cell responses
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
What are the main clinical features of 22q11.2 deletion syndromes?
Congenital cardiac disease
Abnormal facial features - high forehead, low set ears, cleft palate, small mouth and jaw
Thymus hypoplasia
Cleft palate
Hypocalcemia (due to underdeveloped parathyroid)
CATCH 22
immune function improves with age
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 mildy impaired and tends to improve with age
Di George syndrome
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
- Low IgG and IgA –> as no class switching occurs as CD4 cells are necessary for this
Normal CD8 and B cells
Which defect leads to Bare lymphocyte syndrome?
Defects in the regulatory proteins involved in expression of MHC II genes:
- Regulatory factor X
- Class II transactivator
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, IgA
NOTE: BLS Type 1 is a similar condition caused by failure of expression of MHC Class I
HLA = MHC
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
NOTE: disorders of T cell effector function include defects in cytokine production, cytokine receptors and T-B cell communication
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:
- SCID
- Di George
- BLS Type 2
-
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
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.
- X-linked SCID
- IFN-gamma receptor deficiency
- 22q11.2 deletion syndrome
- Bare lymphocyte syndrome type 2
- 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 Mycobacterium 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.
What determines the class of immunoglobulin?
Heavy chain
light chain = kappa or lamda
What determines the effector function of immunoglobulin?
Constant region of the heavy chain
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. complement, phagocytes, NK cells)
- Important in defence against bacteria
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
- Pre B cells can’t mature in B cells, therefore also don’t have antibodies
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
Normal T cells
No B cells
No Ig
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
No class switching can occur
NOTE: CD40 ligand is encoded on Xq26
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)
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
what is most commonly reduced in common varibale immunodeficiency
what do you need to do to be able to diagnose this
Most commonly reduced in IgG
common variable immunodeficiecny is a diagnosis of exclusion –> need to rule out all the other immune conditions first basically e.g. x-linked hyper IgM, selective IgA deficiency
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
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)
What is the prevalence of selective IgA deficiency?
1 in 600
What are the clinical features of antibody deficiency?
- Bacterial infections (e.g. Staphylococcus)
- Toxins (e.g tetanus)
- Some viral infections (e.g. enterovirus)
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 specificpathogen (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
Which peak repesents immunoglobulin in protein electrophoresis?
Gamma peak
NOTE: albumin produces a large peak
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
Outline the management approaches to immunodeficiency involving B cells.
- Aggresive prophylaxis/treatment of infection
- Immunoglobulin replacement
- Immunisation (only if the patient is able to produce antibodies)
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
