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Immunology - Path > Primary immune deficiencies 2 > Flashcards

Primary immune deficiencies 2 Flashcards

1
Q

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

A
  • T lymphocytes - CD4 and CD8 T cells
  • B lymphocytes - B cells, plasma cells and antibodies
  • Soluble components - cytokines and chemokines
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2
Q
  1. What is a primary lymphoid organ?
  2. What are the two main ones and what do they do?
A
  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
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3
Q

Describe B cell development

A

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

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4
Q

Describe the condition Reticular dysgenesis:

  1. What is it?
  2. What is failed to be produced?
  3. Problems with this condition?
A
  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
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5
Q

What are the causes of severe combined immunodeficiency?

A

>20 possible pathways identified:

  • Deficiency of cytokine receptors
  • Deficiency of signalling molecules
  • Metabolic defects
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6
Q

Describe the following about X-linked SCID:

  1. Prevalance
  2. Mutation involved
  3. Phenotype
A
  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
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7
Q
  1. What is ADA deficiency?
  2. What is the phenotype?
A
  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
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8
Q

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

A
  • 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
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9
Q

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

A

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.

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10
Q
  1. What are CD8+ cytotoxic T cells?
  2. What do they do?
A
  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
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11
Q
  1. What do CD4+ helper T cells recognise?
  2. What are the functions of CD4+ T helper cells?
A
  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
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12
Q
  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?
A
  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
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13
Q

Describe how CD4 T cells are affected by MHC II deficiency

A

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

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14
Q
  1. What is bare lymphocyte syndrome - type 2?
  2. What happens to immune cells?
A
  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
  1. 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
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15
Q

What is the clinical phenotype of bare lymphocyte syndrome?

A
  • Unwell by 3 months of age
  • Infections of all types
  • Failure to thrive
  • Family history of early infant death
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16
Q

What are the disorders of T cell effector function?

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

All signalling failures!

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17
Q

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

A
  • 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

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18
Q

What investigations should be done to investigate T cell deficiencies?

A
  • 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
19
Q

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

  1. SCID
  2. DiGeorge
  3. BLS
A
20
Q

What is the management of immunodeficiency involving T cells?

A
  • 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
21
Q

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

A

B. X-linked SCID

22
Q

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

A

D. IFN gamma receptor deficiency

23
Q

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

A

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

24
Q

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

A

A. Bare lymphocyte syndrome type II

25
Q

What are the functions of antibodies?

A
  • 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
26
Q

What is Bruton’s X-linked agammaglobulinaemia?

A
  • 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
27
Q

What is the clinical phenotype of X-linked agammaglobulinaemia?

A
  • 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
28
Q
  1. What is Hyper IgM syndrome?
  2. What is the genetic mutation?
A
  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
29
Q

How does Hyper IgM syndrome affect immune cells?

B cells, T cells, Immunoglobulins

A
  • 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
30
Q

What is the clinical phenotype of hyper IgM syndrome?

A
  • 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
31
Q
  1. What is common variable immune deficiency?
  2. What is it defined by?
A
  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
32
Q

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

A

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
33
Q

What is Selective IgA deficiency?

  1. Prevalence
  2. Clinical phenotype
A
  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

34
Q

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

A
  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
35
Q

What are the clinical features of lymphocyte deficiencies?

A

Antibody deficiency or CD4 T cell deficiency:

  • Bacterial infections - staph, strep
  • Toxins - tetanus, diptheria
  • Some viral infections - Enterovirus
36
Q

What investiagtions should be done for B cell deficiencies?

A
  • 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*
37
Q

In protein electrophoresis, which peak represents the antibodies?

A

Gamma peak shows the antibodies

Someone who is deficient e.g. Bruton’s will have no gamma peak and will be flat

38
Q

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
A
39
Q

What is the management for immunodeficiency involving B cells?

A
  • 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
40
Q

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
A
  1. Common variable immunodeficiency
41
Q

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
A
  1. X-linked hyper IgM syndrome due to CD40 ligand mutations
42
Q

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
A
  1. Bruton’s X-linked hypogammaglobinaemia
43
Q

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
A
  1. IgA deficiency
44
Q
A

Immunology - Path (9 decks)

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