Primary immune deficiencies 2

Question 1

What are the main 3 components of the adaptive immune system?

Answer 1

• T lymphocytes - CD4 and CD8 T cells
• B lymphocytes - B cells, plasma cells and antibodies
• Soluble components - cytokines and chemokines

Question 2

1. What is a primary lymphoid organ?
2. What are the two main ones and what do they do?

Answer 2

1. A primary lymphoid organs are involved in lymphocyte development
2. Bone marrow - Both T and B lymphocytes are derived from haematopoetic stem cells and is the site of B cell maturation. The thymus - site of T cell maturation. Thymus is most active in the foetal and neonatal periods, involutes after puberty

Question 3

Describe B cell development

Answer 3

Stem cells –> lymphoid progenitors then develop to become Pro - B cells –> Pre-B cells –> IgM memory cells can form or go onto mature into plasma cells –> plasma cells produce antibodies

Question 4

Describe the condition Reticular dysgenesis:

1. What is it?
2. What is failed to be produced?
3. Problems with this condition?

Answer 4

1. Reticular dysgenesis is the most severe form of severe combined immunodeficiency (SCID). A mutation in the mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
2. Failure to produce lymphocytes, neutrophils, monocytes/macrophages and platelets - basically everything!
3. Fatal in early life unless corrected with bone marrow transplantation

Question 5

What are the causes of severe combined immunodeficiency?

Answer 5

>20 possible pathways identified:

• Deficiency of cytokine receptors
• Deficiency of signalling molecules
• Metabolic defects

Question 6

Describe the following about X-linked SCID:

1. Prevalance
2. Mutation involved
3. Phenotype

Answer 6

1. 45% of all SCID cases are X-Linked
2. Mutation of common gamma chain on chromosome Xq13.1 - causes inability to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
3. Very low or absent T cell numbers, normal or increased B cells but low Igs, very low or absent NK cells

Question 7

1. What is ADA deficiency?
2. What is the phenotype?

Answer 7

1. Adenosine deaminase deficieny - enzyme lymphocytes are required for cell metabolism. Inability to respond to cytokines causes early arrest of T cells and NK cell developent and production of immature B cells
2. Very low/absent T cell, B cell and NK cell numbers

Question 8

What is the clinical phenotypes of a child with severe combined immunodeficiency?

Answer 8

• Unwell by 3 months of age (protected up to 3 months as still have immunoglobulins from mother in blood)
• Infections of all types
• Failure to thrive
• Persistent diarrhoea
• Unusual skin disease - colonisation of infant’s empty bone marrow by maternal lymphocytes, graft versus host disease
• Family history of early infant death

Question 9

What protects the SCID neonate in the first three months from the classical SCID clinical phenotype?

Answer 9

Maternal IgG can cross the placenta and is therefore a source of circulating IgG in the neonate. These immunoglobulins stay in the blood but decline over time, with most of them disappearing by 3months.

Question 10

1. What are CD8+ cytotoxic T cells?
2. What do they do?

Answer 10

1. CD8+ cytotoxic t cells are specialise cytotoxic cells

2.

• Recognise peptides derived from intracellular proteins in association with HLA class 1
• Kills cells directly - bind to Fas ligand and induces apotosis and through perforin formation and use of granzymes kills cells
• secrete cytokines e.g. interferon gamma, TNFalpha
• Particularly important in defence against viral infections and tumors

Question 11

1. What do CD4+ helper T cells recognise?
2. What are the functions of CD4+ T helper cells?

Answer 11

1. CD4+ T helper cells recognise:

• Peptides derived from extracellular proteins
• Presented on HLA class II molecules

2.

• Immunoregulatory functions via cell:cell interactions and expression of cytokines
• Provides help for development of full B cell response
• Provide help for developmental of some CD8+ T cell responses

Question 12

1. What is DiGeorge syndrome?
2. What chromosomal deletion is involved?
3. What are some of the commo features?
4. How are the immune cells affected?

Answer 12

1. DiGeorge is a deletion syndrome that causes development defect of the pharyngeal pouch, and defects the development of the thymus
2. Deletion is 22q11.2 and is usually sporadic rather than inherited

3.

• High forehead
• Low set, abnormally folded ears, cleft palate, small mouth and jaw
• hypocalcemia
• oesophageal atresia
• underdeveloped thymus

4.

• Normal B cell numbers
• Reduced T cell numbers
• Immune function is usually only mild impaired, and improves with age
• Mainly immunodeficiency in children

Question 13

Describe how CD4 T cells are affected by MHC II deficiency

Answer 13

When there is MHC II deficiency, the thymus cannot actively select CD4 T cells as MHC II is needed to help recognise these cells

Question 14

1. What is bare lymphocyte syndrome - type 2?
2. What happens to immune cells?

Answer 14

1. Bare lymphocyte syndrome is when there is a defect in one of the regulatory proteins involved in class II gene expression can be causing a deficiency in MHC II molecules:

• regulatory factor X
• class II transactivator

2. Profound deficienct of CD4+ cells

• Usually have normal number of CD8+ cells
• Normal number of B cells
• Low IgG or IgA antibody due to lack of CD4+ T cell help - normal IgM

Question 15

What is the clinical phenotype of bare lymphocyte syndrome?

Answer 15

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

Question 16

What are the disorders of T cell effector function?

Answer 16

• Cytokine production affected - IFN
• Cytokine receptor defects - IL12 receptor
• Cytotoxicity
• T-B cell communication defects

All signalling failures!

Question 17

What are the clincal features of lymphocyte deficiences/T cell deficiency?

Answer 17

• Viral infections - Cytomegalovirus
• Fungal infection - pneumocystis, cryptosporidium
• Some bacterial esp. intracellular organisms - mycobacteria tuberculosis, salmonella
• Early malignancy

CD4 T cell cytokines required for control of PCP - hence why life threatening in a patient with HIV

Question 18

What investigations should be done to investigate T cell deficiencies?

Answer 18

• Total white cell count and differential - remember that lymphocyte counts are normally much higher in children than in adults
• Lymphocyte subsets - quantify CD8 T cells, CD4 T cells as well as B cells and NK cells
• Immunoglobulins - if CD4 T cell deficient - an indirect way of looking at T cells - deficienct in T cell will be shown by a lack of IgG and IgA
• Functional tests of T cell activation and proliferation - useful if signalling or activation defects are suspected
• HIV test

Question 19

What are the levels of CD4, CD8, B cell, IgM and IgG for the following conditions?

1. SCID
2. DiGeorge
3. BLS

Answer 19

Question 20

What is the management of immunodeficiency involving T cells?

Answer 20

• Aggressive prophylaxis/treatment of infection
• Haematopoieitic stem cell transplantation - to replace abnormal populations in SCID, and to replace abnormal cells in Class II deficient APs in BLS
• Enzyme replacement therapy - PEG-ADA for ADA-SCID
• Gene therapy - stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo
• Thymic transplantation - to promote T cell differentiation in Di George syndrome

Question 21

Severe recurrent infections from 3 months, CD4 and CD8 T cells absent, B cells present, Igs are low. Normal facial features and cardiac echo.

Choose the most appropriate answer:

A. Bare lymphocyte syndrome type II

B. X-linked SCID

C. 22q11.2 deletion syndrome

D. IFN gamma receptor deficiency

Answer 21

B. X-linked SCID

Question 22

Young adult with chronic infection with mycobacterium marinum

Choose the most appropriate answer:

A. Bare lymphocyte syndrome type II

B. X-linked SCID

C. 22q11.2 deletion syndrome

D. IFN gamma receptor deficiency

Answer 22

D. IFN gamma receptor deficiency

Question 23

Reccurent infections in childhood, abnormal facial features, congenital heart disease, normal B cellsm low T cells, Low IgA and IgG

Choose the most appropriate answer:

A. Bare lymphocyte syndrome type II

B. X-linked SCID

C. 22q11.2 deletion syndrome

D. IFN gamma receptor deficiency

Answer 23

C. 22q11.2 deletion syndrome (DiGeorge syndrome)

Question 24

6 month baby with two recent serious bacterial infections. T cells present - but onlt CD8+ population. B cells present. IgM present but IgG low

Choose the most appropriate answer:

A. Bare lymphocyte syndrome type II

B. X-linked SCID

C. 22q11.2 deletion syndrome

D. IFN gamma receptor deficiency

Answer 24

A. Bare lymphocyte syndrome type II

Question 25

What are the functions of antibodies?

Answer 25

* Identification of pathogens and toxins - Fab mediated * Interact with other components of immune response to remove pathogens - Fc mediated. Inc complement, phagocytes and NK cells * Particularly important in defence against bacteria of all kinds

Question 26

What is Bruton's X-linked agammaglobulinaemia?

Answer 26

* Abnormal B cell tyrosine kinase (BKT) gene. Pre B cells cannot develop to mature B cells * Therefore no circulating mature B cells, and no production of Igs * No circulating Ig after 3 months

Question 27

What is the clinical phenotype of X-linked agammaglobulinaemia?

Answer 27

* Boys present in first few days of life * Recurrent bacterial infections - otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis * viral, fungal, parasitic infections - enterovirus, pneumocystis * Failure to thrive

Question 28

1. What is Hyper IgM syndrome? 2. What is the genetic mutation?

Answer 28

1. Hype IgM syndrome is a T cell ligand problem, and therefore stops T helper cells from helping B cells differentiating 2. Mutation in CD40 ligand gene: * Member of teh TNF receptor family * Encoded on Xq26 * Involved in the T-B cell communication * Expressed by activated T cells - not on B cells

Question 29

How does Hyper IgM syndrome affect immune cells? B cells, T cells, Immunoglobulins

Answer 29

* Normal number of circulating B cells * Normal number of T cells but actuvated cells do NOT express CD40 ligand * No germinal center development within lymph nodes and spleen * Failure of isotype switching * Elevated serum IgM * Undetectable IgA, IgE, IgG

Question 30

What is the clinical phenotype of hyper IgM syndrome?

Answer 30

* Boys present in the first few years of life * Recurrent infections - esp. bacterial * Subtle abnormality in T cell function predisposes to pedisposes to pneumocystis jiroveci infection, autoimmune disease and malignancy * Failure to thrive

Question 31

1. What is common variable immune deficiency? 2. What is it defined by?

Answer 31

1. Heterogenous group of disorders - many different genetic defects, and causes the failure of differentiation/function of B lymphocytes 2. Defined by: * Marked reduction in IgG, with low IgA or IgM * Poor/absent response to immunisation * Absence of other defined immunodeficiency

Question 32

What are the clinical features of common variable immune deficiency in adults and children?

Answer 32

Recurrent bacterial infections * Often with severe end-organ damage * Pneumonia, persistent sinusitis, gastroenteritis Pulmonary disease * Obstructive airways disease * Interstitial lung disease * Granulomatous interstitial lung disease - also lymph and spleen Gastrointestinal disease: * Inflammatory bowel-like disease * Sprue like illness * Bacterial overgrowth Inflammatory disease - airways, GI Autoimmune disease * Autoimmune haemolytic anemia or thrombocytopenia * Rheumatoid arthritis * Pernicious anaemia * Thyroiditis * Vitiligo Malignancy: * Non-Hodgkin lymphoma

Question 33

What is Selective IgA deficiency? 1. Prevalence 2. Clinical phenotype

Answer 33

1. Deficiency only in the production of IgA - prevalence of 1:600 2. 2/3 of individuals are asymptomatic 1/3 have recurrent respiratory tract infections

Question 34

What are the 5 main B cell maturation defects? From stem cell to end product, the defects along the way, and the main effect of the defect

Answer 34

1. Severe combined immune deficiency - Failure of lymphocyte precursors 2. Bruton's X-linked agammaglobulinaemia - Failure of B cell maturation (is BRUTAL - no B cells) 3. X-linked hyper-IgM syndrome - Failure of T cell costimulation 4. Common variable immune deficiency/Selective antibody deficiency - Failure of production of IgG antibodies 5. Selective IgA deficiency - Failure of IgA production

Question 35

What are the clinical features of lymphocyte deficiencies?

Answer 35

Antibody deficiency or CD4 T cell deficiency: * Bacterial infections - staph, strep * Toxins - tetanus, diptheria * Some viral infections - Enterovirus

Question 36

What investiagtions should be done for B cell deficiencies?

Answer 36

* Total white cell count and differential - *remember that lymphocyte counts are normally much higher in children than in adults* * Lymphocyte subsets - *quantify B cells as well as CD4 T cells, CD8 T cells and NK cells* * Serum immunoglobulins and protein electrophoresis - *production of IgG is a surrogate marker for CD4 T cells helper function* * Functional tests of B cell function - *Specific antibody responses to known pathogens* * - Measure IgG antibodies against tetanus, Haemophilus influenzae B and S.pneumoniae* * - If specific antibody levels are low, immunise with he appropriate killed vaccine and repeat antibody measurement 6-8 weeks later* * - Functional tests have generally superceded IgG subclass quantitation*

Question 37

In protein electrophoresis, which peak represents the antibodies?

Answer 37

Gamma peak shows the antibodies Someone who is deficient e.g. Bruton's will have no gamma peak and will be flat

Question 38

Identify whether the following would be increased, decreased or the same for the following conditions: CD4 T cell, CD8 T cell, B cells, IgM, IgG and IgA * SCID * Bruton's X-linked * Hyper IgM X-linked * Selective IgA * CVID

Answer 38

Question 39

What is the management for immunodeficiency involving B cells?

Answer 39

* Aggressive prophylaxis/treatment of infection * Immunoglobulin replacement if required - treatment is life long, contains IgG antibodies to a wide variety of common organisms * Immunisation - for selective IgA deficiency, not otherwise effect because of defect in IgG antibody production

Question 40

EMQ: Which of the following B cell deficiencies match with the following description? An adult with bronchiectasis, recurrent sinusitis and development of atypical SLE 1. IgA deficiency 2. Common Variable immunodeficiencies 3. Bruton's X-linked hypogammaglobulinaemia 4. X-linked hyper-IgM syndrome due to CD40 ligand mutations

Answer 40

2. Common variable immunodeficiency

Question 41

EMQ: Which of the following B cell deficiencies match with the following description? Recurrent bacterial infections in a child, episode of pneumocystitis pneumonia, high IgM, absent IgA and IgG 1. IgA deficiency 2. Common Variable immunodeficiencies 3. Bruton's X-linked hypogammaglobulinaemia 4. X-linked hyper-IgM syndrome due to CD40 ligand mutations

Answer 41

4. X-linked hyper IgM syndrome due to CD40 ligand mutations

Question 42

EMQ: Which of the following B cell deficiencies match with the following description? 1 year old boy, Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent 1. IgA deficiency 2. Common Variable immunodeficiencies 3. Bruton's X-linked hypogammaglobulinaemia 4. X-linked hyper-IgM syndrome due to CD40 ligand mutations

Answer 42

3. Bruton's X-linked hypogammaglobinaemia

Question 43

EMQ: Which of the following B cell deficiencies match with the following description? Recurrent respiratory tract infections, absent IgA, normal IgM and IgG 1. IgA deficiency 2. Common Variable immunodeficiencies 3. Bruton's X-linked hypogammaglobulinaemia 4. X-linked hyper-IgM syndrome due to CD40 ligand mutations

Answer 43

1. IgA deficiency